Colonoscopy—preparation

ABSTRACT

The invention provides a colon cleansing solution comprising: a) 300 to 2000 mmol per litre ascorbate anion provided by ascorbic acid, one or more salts of ascorbic acid, or a mixture thereof; and h) 10 to 200 g per litre polyethylene glycol. The invention also provides methods and kits associated with, or making use of the solutions. The invention also provides a method of cleansing the colon of a subject comprising: —administering to the subject an effect amount of a first cleansing solution; and then after a time interval—administering to the subject an effective amount of a second cleansing solution, wherein the two cleansing solutions are as described in the specification.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is continuation of pending U.S. application Ser. No.16/788,590, filed Feb. 12, 2020, which is a continuation of U.S.application Ser. No. 15/407,080, filed Jan. 16, 2017, and issued as U.S.Pat. No. 10,646,512 on May 12, 2020, which is application a continuationof U.S. application Ser. No. 14/004,604, filed Sep. 11, 2013, and issuedas U.S. Pat. No. 9,592,252 on Mar. 14, 2017, which application is aUnited States national stage filing under 35 U.S.C. § 371 ofinternational (PCT) application no. PCT/GB2012/050526, filed Mar. 9,2012, and designating the United States, application claims priority toUnited Kingdom (GB) Appln. Nos. 1104202.5, filed Mar. 11, 2011;1104200.9, filed Mar. 11, 2011; and 1114629.7, filed Aug. 23, 2011.

The present invention relates to a method of cleansing the colon usingcolon cleansing solutions, and compositions and kits associatedtherewith. Colon cleansing compositions are also known as lavagesolutions, bowel cleansers, purgatives or colonic evacuants.

Colon or bowel cleansing is important before numerous surgical ordiagnostic procedures, including colonoscopy, barium enema examination,sigmoidoscopy and colon surgery. Such procedures are often carried outon an outpatient basis and thus it is desirable that the colon cleansingbe carried out by the patient at home, prior to arrival at the hospitalor surgery where the procedure is to take place. It is thereforeimportant that patient compliance is good without medical supervision ifsatisfactory colon cleansing is to be achieved prior to the procedure.

Intestinal lavage, in which a large volume of an electrolyte solutioncontaining sodium sulphate and polyethylene glycol is ingested, is oneof the most common methods for colon cleansing. These osmotically activeagents are non-absorbable or only poorly absorbable and thus retainwater in the bowel, resulting in copious diarrhea and cleansing of thecolon.

For effective cleansing, many of these compositions must be ingested inquantities of between 2 to 4 litres. The unpleasant taste of thesecompositions combined with the large volumes required to be ingestedoften contributes to nausea or vomiting, resulting in poor patientcompliance and failure to consume the full volume of solution. Poorpatient compliance can lead to inadequate preparation of the colon whichcan, in turn, lead to cancellation or repetition of the colonoscopybecoming necessary or, worse, non-detection of lesions or polypsindicative of cancer risk.

A number of improved colon cleansing compositions are described in WO2004/037292. A colon cleansing composition according to WO 2004/037292that comprises polyethylene glycol 3350, sodium sulphate, an ascorbatecomponent, electrolytes, sweetener and flavouring is commercialised as apowder for oral solution under the tradename MOVIPREP® (registeredtrademark of Velinor AG, a member of the Norgine group of companies).The MOVIPREP solution is effective despite being taken in asubstantially lower volume than other colon cleansing solutions.Typically, only 2 litres of the solution need to be taken by an adultpatient, a significant benefit when compared to taking 4 litres ofprevious solutions.

Various regimens for the timing of ingestion of colon cleansingsolutions are mentioned in the literature and in patient informationleaflets that accompany colon cleansing products. For example, theMOVIPREP solution mentioned above may be taken (optionally withadditional clear liquids also optionally being taken) in the eveningbefore the examination or procedure, or the MOVIPREP solution may betaken in a “split-dose” regimen, with approximately half of thecleansing solution being taken the evening before the examination orprocedure (“first dose”), and the remainder being taken the followingmorning (“second dose”).

Despite the advances that have been made, all colon cleansing productson the market continue to require a subject to ingest a large volume ofsolution (2 litres in the case of the MOVIPREP solution). Many subjectsfind the ingestion of a large volume unpleasant or difficult and poorpatient compliance thus remains a problem. There remains a need foralternative colon cleansing solutions that are effective when ingestedin small volumes.

When comparing the pharmacokinetic profiles of the components of theMOVIPREP solution (ascorbate component, sodium sulphate, PEG 3350 andelectrolytes) in subjects who had taken the solution in the “eveningbefore” regimen with the pharmacokinetic profiles in subjects who hadtaken the solution in the “split-dose” regimen in a clinical study, thepresent inventors found that a surprisingly high proportion of theascorbate component of the first dose of the “split-dose” regimen wasabsorbed into the subjects' circulations. The proportion of theascorbate component that was found to be absorbed into the circulationwas then excreted in the subjects' urine over time, rather than beingexpelled in faeces. Whilst this absorption into the circulation is notharmful to the subject, it does reduce the osmotic strength of thesolution, and hence it reduces the solution's ability to cleanse thecolon. It is also wasteful of the component. The finding was surprisingin view of the commonly accepted view in the literature that a maximumof 3 g of ascorbic acid can be absorbed in the intestines per day(Hornig, D. et al., Int. J. Vit. Nutr. Res., 1980, 50, 309).Ascorbate-containing colon cleansing solutions have to date beenformulated on that basis.

The invention thus provides, in a first aspect, a colon cleansingsolution comprising:

a) 300 to 2000 mmol per litre ascorbate anion provided by ascorbic acid,one or more salts of ascorbic acid, or a mixture thereof; and

b) 10 to 200 g per litre polyethylene glycol.

The solution of the invention is a surprisingly effective coloncleansing solution as measured by stool output, providing satisfactoryclearance of stools from the colon with ingestion of a smaller totalvolume of solution than with the standard 2 or 4 litre solutions of theprior art.

The ascorbate anion may be provided by ascorbic acid, by one or moresalts of ascorbic acid, or by a mixture of ascorbic acid and one or moresalts of ascorbic acid. For convenience, they will be referred to hereinas the “ascorbate component”. Suitable salts include alkali metal saltsand alkaline earth metal salts. For example a salt may be selected fromsodium, potassium, magnesium and calcium salts. For example, preferredsalts of ascorbic acid include sodium ascorbate, potassium ascorbate,magnesium ascorbate and calcium ascorbate. In an embodiment, theascorbate anion is provided by ascorbic acid, one or more salts ofascorbic acid selected from sodium ascorbate, potassium ascorbate,magnesium ascorbate and calcium ascorbate, or a mixture thereof.Particularly preferred salts of ascorbic acid are magnesium ascorbateand sodium ascorbate, for example sodium ascorbate. In one embodiment,the solution comprises ascorbic acid and one or more salts of ascorbicacid (and preferably no further ascorbate), for example ascorbic acidand sodium ascorbate (and preferably no further ascorbate), or ascorbicacid and magnesium ascorbate (and preferably no further ascorbate).

The solution of the invention preferably comprises ascorbate anion in aconcentration of: 300-1500 mmol per litre, for example 300-1200 mmol perlitre, for example 300-1000 mmol per litre, for example 300-850 mmol perlitre, for example 350-800 mmol per litre, for example 400-700 mmol perlitre.

Ascorbic acid has a molecular weight of 176 g/mol. Accordingly, the 300to 2000 mmol ascorbate anion per litre can be provided by 52.8 to 352g/litre ascorbic acid.

Sodium ascorbate has a molecular weight of 198 g/mol. Accordingly, the300 to 2000 mmol ascorbate anion per litre can be provided by 59.4 to396 g/litre sodium ascorbate.

Potassium ascorbate has a molecular weight of 214 g/mol. Accordingly,the 300 to 2000 mmol ascorbate anion per litre can be provided by 64.2to 428 g/litre potassium ascorbate.

Magnesium ascorbate has a molecular weight of 374.5 g/mol and each moleof magnesium ascorbate provides two moles of ascorbate. Accordingly, the300 to 2000 mmol ascorbate anion per litre can be provided by 56.2 to374.5 g/litre magnesium ascorbate.

Depending on the pH of the solution, some ascorbate anion may beprotonated and thus exist as free ascorbic acid. At the pH of solutionsthat would typically be administered, only a very minor proportion ofascorbate is protonated. In calculations of concentrations of “ascorbateanion” herein, the concentration of “ascorbate anion” is taken as thetotal concentration of all ascorbate anion present, including theproportion that is protonated.

A solution of the invention comprises 50 to 450 g/litre of an ascorbatecomponent, the ascorbate component being ascorbic acid, one or moresalts of ascorbic acid or a mixture of ascorbic acid and one or moresalts of ascorbic acid. For example, a solution of the inventioncomprises 50 to 300 g/litre of ascorbate component, for example 50 to200 g/litre, for example 60 to 150 g/litre, for example 60 to 120g/litre, for example 80 to 120 g/litre, for example 100 to 120 g/litre.

In an embodiment, the ascorbate component consists essentially of sodiumascorbate alone. For example, it may be present in an amount asmentioned immediately above.

In an alternative embodiment, the ascorbate component comprises (orconsists essentially of) sodium ascorbate and ascorbic acid. Forexample, they may be present in a total amount as mentioned immediatelyabove. They may be in a weight ratio of sodium ascorbate:ascorbic acidfrom 1:10 to 10:1, for example 2:8 to 8:2, for example 3:7 to 7:3, forexample 1.4:1 to 1.8:1.

In an alternative embodiment, the ascorbate component comprises (orconsists essentially of) of sodium ascorbate and magnesium ascorbate.For example, they may be present in a total amount as mentionedimmediately above. They may be in a weight ratio of sodiumascorbate:magnesium ascorbate from 1:10 to 10:1, for example 2:8 to 8:2,for example 3:7 to 7:3, for example 1.8:1 to 1.4:1.

The cleansing solution comprises polyethylene glycol. The polyethyleneglycol (PEG) may, for example, have an average molecular weight of 2000to 8000, for example 2500 to 4500 Da, for example 3000 to 4000 Da. Forexample, the PEG may be PEG 3350 or PEG 4000 as defined in nationalpharmacopeias. Further examples of suitable PEGs recognized in somenational pharmacopeias include Macrogols, for example Macrogol 3350 orMacrogol 4000.

The cleansing solution comprises 10 to 200 g per litre of PEG.Preferably, the solution comprises 10 to 160 g per litre of PEG, morepreferably 10 to 120 g per litre, for example 20 to 100 g per litre, forexample 30 to 90 g per litre, for example 40 g per litre or 80 g perlitre.

The cleansing solution may additionally comprise one or more of:

c) one or more electrolytes;

d) one or more alkali metal or alkaline earth metal sulphates;

e) one or more flavouring agents;

f) one or more sweeteners.

The cleansing solution may comprise one or more electrolytes.Electrolytes include salts of sodium, potassium, calcium and magnesium,particularly sodium and potassium; and salts of chloride, iodide,bicarbonate and carbonate, particularly chloride. Preferred electrolytesare sodium chloride and potassium chloride. In an embodiment, thesolution is substantially free from sodium bicarbonate.

For example, the solution may comprise sodium chloride at aconcentration of 1 to 10 g per litre. For example, sodium chloride maybe present at a concentration of 2 to 8 g per litre, for example 3 to 7g per litre.

For example, the solution may comprise potassium chloride at aconcentration of 1 to 10 g per litre. For example, potassium chloridemay be present at a concentration of 1 to 8 g per litre, for example 1.5to 6 g per litre, for example 2 to 5 g per litre.

In an embodiment, the solution comprises sodium chloride and potassiumchloride. They can be present in the amounts mentioned immediatelyabove. For example, sodium chloride may be present at a concentration of3 to 7 g per litre and potassium chloride may be present at aconcentration of 2 to 5 g per litre.

The cleansing solution may comprise one or more alkali metal sulphates,alkaline earth metal sulphates or a mixture thereof (herein referred toas a “sulphate component”). An alkali metal or alkaline earth metalsulphate may, for example, be selected from sodium sulphate, potassiumsulphate and magnesium sulphate. The solution may comprise more than oneof sodium sulphate, potassium sulphate and magnesium sulphate, forexample all three. Preferably, the sulphate component is or includessodium sulphate. In an embodiment, the solution does not comprise asulphate component.

For example, the solution may comprise a sulphate component at aconcentration of 2 to 20 g per litre, for example 5 to 15 g per litre,for example 8 to 15 g per litre, for example 10 to 14 g per litre, forexample 12 g per litre. The one or more sulphate salts may be providedin any pharmaceutically acceptable form: they may each be anhydrous, orbe in a hydrated form. The weights mentioned herein refer to the weightof the sulphate salt excluding any water of hydration.

In the solutions of the invention described herein, the quantities ofthe individual components recited do not include any solutes that may bepresent in the water used to prepare the solutions, for example, in hardwater areas there may be significant amounts of Ca′ and Mg′ carbonates,bicarbonates or sulphates present in tap water.

The cleansing solution preferably includes a flavouring agent. Aflavouring for use in compositions of the invention should preferablymask saltiness, be relatively sweet but not excessively so, and bestable in the composition. A flavouring makes the solutions morepalatable and thus aids patient compliance. Preferred flavouringsinclude lemon e.g. Ungerer Lemon (available from Ungerer Limited,Sealand Road, Chester, England CH1 4LP) strawberry e.g. UngererStrawberry, grapefruit e.g. Ungerer Grapefruit flavouring powder,blackcurrant e.g. Ungerer Blackcurrant, pineapple e.g. IFF(International Flavours and Fragrances) Pineapple flavouring powder andvanilla/lemon and lime e.g. IFF Vanilla and Givaudin Roure Lemon andLime Flav-o-lok. Those and further suitable flavourings are availablefrom International Flavours and Fragrances Inc. (Duddery Hill,Haverhill, Suffolk, CB9 8LG, England), Ungerer & Company (Sealand Road,Chester, England CH1 4LP) or Firmenich (Firmenich UK Ltd., Hayes Road,Southall, Middlesex UB2 5NN). More preferred flavourings are lemon,kiwi, strawberry and grapefruit.

The amount of flavouring required depends on the nature and strength ofthe flavouring in question. Typically, it is 0.05 to 2.0 g per litre.

The cleansing solution preferably includes a sweetener. Sugar-basedsweeteners are generally not suited for colon cleansing compositionsbecause the delivery of unabsorbed sugars to the colon provides asubstrate for bacteria. Such sugars may be metabolised by the bacteriato form explosive gases such as hydrogen and methane. The presence ofexplosive gases in the colon can be highly dangerous when electricalapparatus is to be used during colonoscopy or other procedures.Preferred sweeteners include aspartame, acesulfame potassium (acesulfameK), sucralose and saccharine, and/or combinations thereof. For example,compositions of the invention may comprise one or both of aspartame andacesulfame potassium (acesulfame K). For example, compositions of theinvention may comprise one or both of sucralose and acesulfame potassium(acesulfame K). Alternatively, compositions of the invention can besubstantially free from added sweeteners, for example to minimize thenumber of different components in the compositions. Citric acid may alsobe present as a taste enhancer. Citric acid and/or salts thereof mayreplace some or all of the ascorbate in solutions of the invention.

The amount of sweetener required depends on the nature and strength ofthe sweetener being considered. Typically, it is 0.10 to 1.0 g perlitre.

The invention thus provides a colon cleansing solution comprising:

a) 300 to 2000 mmol per litre ascorbate anion;

b) 10 to 200 g per litre PEG.

c) one or more electrolytes;

d) optionally one or more alkali metal or alkaline earth metalsulphates;

e) optionally one or more flavouring agents; and

f) optionally one or more sweeteners.

In particular, the invention provides a colon cleansing solutioncomprising (or consisting essentially of water and):

a) 300 to 2000 mmol per litre ascorbate anion;

b) 10 to 200 g per litre PEG having an average molecular weight of 3000to 4000 Da;

c) sodium chloride and potassium chloride;

d) optionally sodium sulphate;

e) optionally one or more flavouring agents; and

f) optionally one or more sweeteners.

Each of c) and d) may be present in the concentrations described above.Each of e) and f) may be as described above and/or be in theconcentrations described above.

In particular, the invention provides a colon cleansing solutioncomprising (or consisting essentially of water and):

a) 300 to 2000 mmol per litre ascorbate anion;

b) 10 to 200 g per litre PEG having an average molecular weight of 3000to 4000 Da;

c) sodium chloride and potassium chloride;

e) one or more flavouring agents; and

f) one or more sweeteners.

In one embodiment, the one or more components of c), d) e) and f) arepresent in the solution. In an alternative presentation, some or all ofcomponents c), d) e) and f) may be provided separately from thesolution, for example in a tablet or capsule. In an embodiment, thesolution may comprise a) the ascorbate component and b) PEG, andoptional flavouring and sweetener (e) and f)), and a tablet or capsulemay comprise c) the one or more electrolytes and/or d) the one or morealkali metal or alkaline earth metal sulphates, again with optionalflavouring and sweetener (e) and f)). The flavouring and sweeteners neednot be the same in the tablet or capsule as in the solution.

In general it is not necessary for the solutions to includepreservatives or anti-oxidants. Nevertheless, low levels ofanti-oxidants or preservatives may be used if required.

Preferably, the colon cleansing solution is hyper-osmotic. That is tosay that it has a higher osmotic strength than blood in the human body.It may, for example have a measured osmolality in the range 500 to 2000mOsmol/kg. For example, the osmolality may be in the range 700 to 1800mOsmol/kg, for example 800 to 1700 mOsmol/kg, for example 900 to 1600mOsmol/kg, for example 900 to 1300 mOsmol/kg, for example 1000 to 1300mOsmol/kg.

Osmolality can be measured in various ways. In general, either freezingpoint depression or vapour-pressure alteration is used. For example, anAdvanced Instruments, Inc Model 3250 osmometer (a freezing pointdepression device) can be used. Vapour pressure measurement can also beused, for example using an ELITech Group Vapro 5600 device. Osmolalityvalues cited herein are preferably taken to be values measured using afreezing point depression osmometer, for example using an AdvancedInstruments, Inc Model 3250 osmometer following standard operatingprocedure.

When carrying out a bowel cleansing treatment, a subject typically takesa single dose or a split dose of cleansing solution. In a split-dosetreatment, typically two doses are taken separated by a time interval,for example an overnight interval. Each dose in a split dose treatmentis smaller than the dose in the single dose treatment. In a split dosetreatment, the two doses may each have the same composition, or they maybe different.

For a single dose treatment, the solution of the invention may be takenin a volume of 700 to 1500 ml. For example, the subject may take from750 ml to 1300 ml of the solution, for example 800 to 1200 ml, forexample 900 to 1100 ml, for example 1000 ml. In an embodiment, thesubject may take some additional clear fluid. The additional clear fluidmay be taken after taking the solution. Alternatively, the additionalclear fluid may be co-administered with the intake of the solution ofthe invention. By “co-administered” is meant the coordinatedadministration of a solution of the invention with clear fluid.

For a split dose treatment, the solution of the invention may be takenwith one of the doses having a volume of 200 to 1000 ml. For example,the subject may take 300 ml to 1000 ml of the solution, for example 300ml to 900 ml, for example 300 ml to 800 ml, for example 400 ml to 700ml, for example 400 to 600 ml, for example 450 to 550 ml, for example500 ml. In an embodiment, the subject may take some additional clearfluid with each or either dose the solution of the invention. Theadditional clear fluid may be taken after taking a dose of the solution.Alternatively, the additional clear fluid may be co-administered withthe intake of a dose of the solution of the invention.

In a split dose treatment, the solution of the invention may be takenfor one or for both of the doses. Preferably, the solution of theinvention is taken as the second solution. The first solution may thenbe a solution of different constitution from the second solution. Thus,in a preferred embodiment of a split dose bowel cleansing treatment, asubject takes a dose of an initial cleansing solution, optionallyfollowed by some additional clear fluid. After an interval, the subjectthen takes a dose of the solution of the invention, optionally followedby some additional clear fluid.

The volume of clear fluid that a subject takes after the first or seconddose may be in a range with a lower limit of 100 ml, 200 ml, 300 ml, 400ml or 500 ml. Preferably, the lower limit is 300 ml, 400 ml or 500 ml.The volume may be in a range with an upper limit of 1200 ml, 1100 ml,1000 ml, 900 ml or 800 ml. For example the volume may be in the range100 ml to 1200 ml, for example 200 ml to 1100 ml, for example 300 ml to1000 ml, for example 500 ml to 900 ml, for example 875 ml, for example500 ml to 800 ml. The instructions provided to the subject may suggestthat the additional clear fluid is ingested over a period ofapproximately one hour, for example in 150 to 200 ml fractions every 15to 20 minutes. The additional clear fluid may be taken after taking adose of the solution. Alternatively, the additional clear fluid may beco-administered with the intake of a dose of the solution of theinvention.

A clear fluid for taking as the additional clear fluid, or for use asthe clear fluid when making up a solution, may be any fluid that allowsinspection of colonic output. The clear fluid should also not impedeinspection of the colon during the colonoscopy. Typically the clearfluid is a water-based beverage, including, for example, water,lemonade, cola drinks, cordial drinks, clear fruit juices and even clearalcohol-containing beverages, for example beer. It is desirable that theclear fluid does not contain substantial amounts of or essentially anydietary fibre, as such fibre interferes with the cleansing of the colonaccording to the present invention. Accordingly, fruit juices, forexample orange juice and kiwi juice, and fruit “squashes” should bestrained before use. Clear fruit cordials, for example, lime cordial,are generally suitable. In view of the desirability of avoiding drinkscontaining glucose, so as to reduce the risk of explosive concentrationsof hydrogen or methane building up in the gut, “diet” drinks containingno or low sugar are especially suitable, for example liquid drinks fordiabetics, diet Coke®, diet lemonade, dietary carbonated drinks ordietary cordials.

The invention further provides a composition (for example a drycomposition, for example a powder) for the preparation of a solution ofthe invention. A composition can be provided in a quantity for thepreparation of a dose of the solution, for example a 500 ml dose. Theinvention provides a composition for admixture with water, wherein thecomposition is optionally presented in two or more parts and comprises:

a) 150 to 1000 mmol ascorbate anion provided by ascorbic acid, one ormore salts of ascorbic acid, or a mixture thereof; and

b) 5 to 100 g polyethylene glycol.

For example, the components may be in dry powder, granular or other dryform. They may alternatively be in the form of concentrates or slurries.Components may be in the same or different physical forms. For example,the composition is a dry composition, for example a dry powdercomposition. For example, one or both of components a) and b) are drypowders.

As set out above, the ascorbate anion may be provided by ascorbic acid,by one or more salts of ascorbic acid, or by a mixture of ascorbic acidand one or more salts of ascorbic acid. Preferred forms of the ascorbatecomponent are as set out above in relation to solutions of theinvention.

The composition of the invention preferably comprises ascorbate anion inan amount of: 150 to 750 mmol, for example 150 to 600 mmol, for example150 to 500 mmol, for example 150 to 425 mmol, for example 175-400 mmol,for example 200-350 mmol.

Ascorbic acid has a molecular weight of 176 g/mol. Accordingly, the 150to 1000 mmol ascorbate anion can be provided by 26.4 to 176 g ascorbicacid.

Sodium ascorbate has a molecular weight of 198 g/mol. Accordingly, the150 to 1000 mmol ascorbate anion can be provided by 29.7 to 198 g sodiumascorbate.

Potassium ascorbate has a molecular weight of 214 g/mol. Accordingly,the 150 to 1000 mmol ascorbate anion can be provided by 32.1 to 214 gpotassium ascorbate.

Magnesium ascorbate has a molecular weight of 374.5 g/mol and each moleof magnesium ascorbate provides two moles of ascorbate. Accordingly, the150 to 1000 mmol ascorbate anion can be provided by 28.1 to 187.25 gmagnesium ascorbate.

In solid form, ascorbic acid is typically made up of protonated freeascorbic acid. In calculations of concentrations of “ascorbate anion”herein, the number of moles of “ascorbate anion” is taken as the totalconcentration of all ascorbate anion present, including the proportionthat is protonated.

The weight of the ascorbate component may be 20 to 220 g, for example 20to 150 g, for example 20 to 100 g, for example 25 to 220 g, for example25 to 150 g, for example 25 to 100 g, for example 25 to 75 g, forexample 20 to 60 g, for example 50 to 60 g.

In an embodiment, the ascorbate component consists essentially of sodiumascorbate alone. For example, it may be present in an amount asmentioned immediately above.

In an alternative embodiment, the ascorbate component comprises (orconsists essentially of) sodium ascorbate and ascorbic acid. Forexample, they may be present in a total amount as mentioned immediatelyabove. They may be in a weight ratio of sodium ascorbate:ascorbic acidfrom 1:10 to 10:1, for example 2:8 to 8:2, for example 3:7 to 7:3, forexample 1.4:1 to 1.8:1.

In an alternative embodiment, the ascorbate component comprises (orconsists essentially of) sodium ascorbate and magnesium ascorbate. Forexample, they may be present in a total amount as mentioned immediatelyabove. They may be in a weight ratio of sodium ascorbate:magnesiumascorbate from 1:10 to 10:1, for example 2:8 to 8:2, for example 3:7 to7:3, for example 1.8:1 to 1.4:1.

Preferred forms of the PEG are as set out above in relation to solutionsof the invention. The composition comprises 5 to 100 g of PEG.Preferably, the composition comprises 5 to 80 g of PEG, more preferably5 to 60 g, for example 10 to 50 g, for example 15 to 45 g, for example20 g or 40 g of PEG.

The composition may additionally comprise one or more of:

c) one or more electrolytes;

d) one or more alkali metal or alkaline earth metal sulphates;

e) one or more flavouring agents; and

f) one or more sweeteners.

Preferred electrolytes are as set out above in relation to solutions ofthe invention. For example, the composition may comprise sodium chloridein an amount of 0.5 to 5 g, for example 1 to 4 g, for example 1.5 to 3.5g. For example, the composition may comprise potassium chloride in anamount of 0.5 to 5 g, for example 0.5 to 4 g, for example 0.75 to 3 g,for example 1.0 to 2.5 g.

Preferred alkali metal or alkaline earth metal sulphates are as set outabove in relation to solutions of the invention. For example, thecomposition may comprise a sulphate component in an amount of 1 to 10 g,for example 2.5 to 7.5 g, for example 4 to 7.5 g, for example 5 to 7 g,for example 6 g. The one or more sulphate salts may be provided in anypharmaceutically acceptable form: they may each be anhydrous, or be in ahydrated form. The weights mentioned herein refer to the weight of thesulphate salt excluding any water of hydration.

Preferred flavouring agents are as set out above in relation tosolutions of the invention. For example the amount of flavouring agentmay be 0.025 to 1.0 g.

Preferred sweeteners are as set out above in relation to solutions ofthe invention. For example the amount of sweetener may be 0.05 to 0.5 g.

In particular, the invention provides a composition comprising (orconsisting essentially of):

a) 150 to 1000 mmol ascorbate anion;

b) 5 to 100 g PEG having an average molecular weight of 3000 to 4000 Da.

c) sodium chloride and potassium chloride;

d) optionally sodium sulphate;

e) optionally one or more flavouring agents;

f) optionally one or more sweeteners.

Each of c) and d) may be present in the amounts described above. Each ofe) and f) may be as described above and/or be in the amounts describedabove.

In one embodiment, the one or more components of c), d) e) and f) arepresent in the composition for making up a solution. In an alternativepresentation, some or all of components c), d) e) and f) may be providedseparately from the composition for making up the solution, for examplein a tablet or capsule. In an embodiment, there may be provided theascorbate component and PEG, and optional flavouring and sweetener, in aform for admixture with water, and a tablet or capsule comprising theone or more electrolytes and/or the one or more alkali metal or alkalineearth metal sulphates, again with optional flavouring and sweetener. Theflavouring and sweeteners need not be the same in the tablet or capsuleas in the composition for admixture with water.

In some embodiments, it is desirable to package the ascorbate and thePEG components separately from each other.

In an embodiment, the composition can be provided to the subject with aplurality of flavouring agents (each optionally with one or moresweeteners), each separately packaged. The subject can then select apreferred flavouring (or flavouring and sweetener combination) accordingto his or her taste. The subject also has the choice of not using anyflavouring or sweetener at all.

In a further aspect, the invention provides a composition comprising thefollowing components in the following weight ratios:

a) ascorbate 0.82 to 10.0 parts; and

b) polyethylene glycol 1.0 part.

As mentioned above, for example, the components may be in dry powder,granular or other dry form. They may alternatively be in the form ofconcentrates or slurries. Components may be in the same or differentphysical forms. For example, the composition is a dry composition, forexample a dry powder composition. For example, one or both of componentsa) and b) are dry powders.

As set out above, the ascorbate anion may be provided by ascorbic acid,by one or more salts of ascorbic acid, or by a mixture of ascorbic acidand one or more salts of ascorbic acid. Preferred forms of the ascorbatecomponent are as set out above in relation to solutions of theinvention.

Preferred forms of the PEG are as set out above in relation to solutionsof the invention. The composition of the invention preferably comprisesascorbate anion in a weight ratio to PEG of 0.82 to 5.0:1. Morepreferably, the weight ratio is 0.9 to 5.0:1, for example 1.0 to 4.0:1,for example 1.0 to 3.0:1, for example 1 to 2:1, or 2 to 3:1.

The composition may additionally comprise one or more of:

c) one or more electrolytes;

d) one or more alkali metal or alkaline earth metal sulphates;

e) one or more flavouring agents;

f) one or more sweeteners.

Preferred electrolytes are as set out above in relation to solutions ofthe invention. For example, the composition may comprise sodium chloridein a weight ratio to PEG of 0.005 to 1.0:1, for example 0.01 to 0.6:1,for example 0.03 to 0.5:1, for example 0.04 to 0.4:1, for example 0.05to 0.3:1, for example 0.06 to 0.2:1. For example, the composition maycomprise potassium chloride in a weight ratio to PEG of 0.005 to 1.0:1,for example 0.005 to 0.50:1, for example 0.01 to 0.50:1, for example0.01 to 0.10:1, for example 0.02 to 0.08:1, for example 0.03 to 0.07:1.

For example, the invention provides a composition comprising thefollowing components in the following weight ratios:

a) ascorbate anion: 0.82 to 10.0 parts;

b) polyethylene glycol: 1.0 part;

c1) sodium chloride: 0.005 to 1.0 parts; and

c2) potassium chloride: 0.005 to 1.0 parts.

The composition is preferably substantially free from sodiumbicarbonate. For example, it is substantially free from any bicarbonate.

Preferred alkali metal or alkaline earth metal sulphates are as set outabove in relation to solutions of the invention. For example, thecomposition may comprise a sulphate component (for example sodiumsulphate) in a weight ratio to PEG of 0.01 to 0.50:1, For example, thecomposition may comprise a sulphate component (for example sodiumsulphate) in a weight ratio to PEG of 0.02 to 0.25:1, for example 0.03to 0.22:1, for example 0.05 to 0.20:1, for example 0.10 to 0.20:1.

Preferred flavouring agents are as set out above in relation tosolutions of the invention. For example the composition may comprise aflavouring agent in a weight ratio to PEG of 0.0005 to 0.025:1, forexample 0.001 to 0.025:1, for example 0.003 to 0.010:1.

Preferred sweeteners are as set out above in relation to solutions ofthe invention. For example the composition may comprise a sweetener in aweight ratio to PEG of 0.0005 to 0.025:1, for example 0.001 to 0.025:1,for example 0.002 to 0.010:1.

In particular, the invention provides a composition comprising (orconsisting essentially of) the following components in the followingweight ratios:

a) ascorbate anion: 0.82 to 10.0 parts

b) having an average molecular weight of 3000 to 4000 Da: 1.0 part.

c) sodium chloride and potassium chloride;

d) optionally sodium sulphate;

e) optionally one or more flavouring agents; and

f) optionally one or more sweeteners.

Each of c) and d) may be present in the weight ratios to PEG describedabove. Each of e) and f) may be as described above and/or be in theweight ratios to PEG described above.

Preferred compositions of the invention are dry compositions, forexample dry powder compositions.

As mentioned above, the solutions of the invention find use in cleansingthe colon. The invention thus provides, in a second aspect a solution inwater of:

a) 300 to 2000 mmol per litre ascorbate anion provided by ascorbic acid,one or more salts of ascorbic acid, or a mixture thereof; and

b) optionally 10 to 200 g per litre polyethylene glycol, for use incleansing the colon of a mammal.

The solution for use in cleansing the colon of a mammal preferablycomprises ascorbate anion in a concentration of: 300-1500 mmol perlitre, for example 300-1200 mmol per litre, for example 300-1000 mmolper litre, for example 300-850 mmol per litre, for example 350-800 mmolper litre, for example 400-700 mmol per litre. As set out above, theascorbate anion may be provided by ascorbic acid, by one or more saltsof ascorbic acid, or by a mixture of ascorbic acid and one or more saltsof ascorbic acid. Preferred forms of the ascorbate component are as setout above in relation to solutions of the invention.

In a preferred embodiment, PEG is present. Preferred forms of the PEGand preferred amounts thereof are as set out above in relation tosolutions of the invention.

The solution for use in cleansing the colon of a mammal may additionallycomprise one or more of:

c) one or more electrolytes;

d) one or more alkali metal or alkaline earth metal sulphates;

e) one or more flavouring agents;

f) one or more sweeteners.

Preferred electrolytes and preferred amounts thereof are as set outabove in relation to solutions of the invention.

Preferred alkali metal or alkaline earth metal sulphates and preferredamounts thereof are as set out above in relation to solutions of theinvention.

Preferred flavouring agents and preferred amounts thereof are as set outabove in relation to solutions of the invention.

Preferred sweeteners and preferred amounts thereof are as set out abovein relation to solutions of the invention.

For example, the solution in water comprises:

a) 150 to 1000 mmol ascorbate anion; and

b) optionally 5 to 100 g PEG.

In particular, the invention provides a solution comprising (orconsisting essentially of water and):

a) 150 to 1000 mmol ascorbate anion;

b) 5 to 100 g PEG having an average molecular weight of 3000 to 4000 Da;

c) sodium chloride and potassium chloride;

d) optionally sodium sulphate;

e) optionally one or more flavouring agents; and

f) optionally one or more sweeteners for use in cleansing the colon of amammal.

Each of c) and d) may be as described above and/or be present in theamounts described above in relation to solutions of the invention. Eachof e) and f) may be as described above and/or be in the amountsdescribed above.

As mentioned above, a bowel cleansing treatment typically involves asubject taking a single dose or a split dose of cleansing solution. Thevolume of solution that a subject takes in a single dose treatment isdescribed hereinabove. The subject may take some additional clear fluidafter taking the solution as described hereinabove.

The volume of solution that a subject takes in a split dose treatment isdescribed hereinabove. The subject may take some additional clear fluidafter each or either dose the solution as described hereinabove.

The solutions and compositions of the invention find particular use insplit dose colon cleansing treatments in which the subject takes twodifferent solutions: a first colon cleansing solution, followed by asecond colon cleansing solution. Preferably, the solution of theinvention is the second colon cleansing solution. Alternatively, it maybe the first solution. The invention thus provides a method of cleansingthe colon of a mammal comprising:

-   -   the subject taking an effective amount of a first colon        cleansing solution;    -   the subject taking an effective amount of a second colon        cleansing solution,

the second colon cleansing solution being a solution comprising

a) 300 to 2000 mmol per litre ascorbate; and

b) optionally 10 to 200 g per litre polyethylene glycol.

The method of the invention may be used to cleanse the colon prior tocarrying out a diagnostic, therapeutic or surgical procedure on thecolon, rectum or anus or elsewhere in the abdomen. The diagnostic orsurgical procedure may, for example, be colonoscopy, barium enemaexamination, sigmoidoscopy or colon surgery. Preferably, the firstsolution is of different composition from the second.

The invention further provides a method of conducting a diagnostic orsurgical procedure, for example, a colonoscopy, barium enemaexamination, sigmoidoscopy or colon surgery, comprising the steps of:

a) cleansing the colon by a method of the invention, and then

b) carrying out the diagnostic or surgical procedure.

The invention provides a kit comprising:

-   -   a first colon cleansing solution, and    -   a second colon cleansing solution,

the second colon cleansing solution being a solution in water of:

a) 300 to 2000 mmol per litre ascorbate anion provided by ascorbic acid,one or more salts of ascorbic acid, or a mixture thereof; and

b) optionally 10 to 200 g per litre polyethylene glycol.

In an embodiment, the first solution is different from the second. Thekit may comprise instructions for use.

The invention further provides a first colon solution, and a secondcolon solution, for use in a method of cleansing the colon comprising:

-   -   the subject taking an effective amount of a first colon        cleansing solution;    -   the subject taking an effective amount of a second colon        cleansing solution,

the second colon cleansing solution being a solution in water of:

a) 300 to 2000 mmol per litre ascorbate anion provided by ascorbic acid,one or more salts of ascorbic acid, or a mixture thereof; and

b) optionally 10 to 200 g per litre polyethylene glycol.

In an embodiment, the first solution is different from the second.

The second colon cleansing solution is preferably as describedhereinabove in relation to solutions and uses of the first aspect of theinvention. It is preferably used in a volume as described hereinabove inrelation to solutions and uses of the invention.

The first cleansing solution may, for example, be a bowel contentsuspending agent. The first cleansing solution may comprise polyethyleneglycol and/or an alkali metal sulphate, an alkaline earth metal sulphateor a mixture thereof. The first cleansing solution may be hyper-osmotic.

Preferably, the first colon cleansing solution comprises polyethyleneglycol (PEG). The polyethylene glycol (PEG) may have an averagemolecular weight of 2000 to 8000, for example 2500 to 4500 Da, forexample 3000 to 4000 Da. For example, the PEG may be PEG 3350 or PEG4000 as defined in national pharmacopeias. Further examples of suitablePEGs recognized in some national pharmacopeias include Macrogols, forexample Macrogol 3350 or Macrogol 4000.

Preferably, the first colon cleansing solution comprises 70 to 250 g perlitre of PEG. Preferably, the solution comprises 130 to 250 g per litrePEG, for example 90 to 200 g per litre of PEG, more preferably 100 to200 g per litre, for example 120 to 150 g per litre, for example 133.3 gper litre.

Preferably, the first colon cleansing solution comprises one or morealkali metal sulphates, alkaline earth metal sulphates or a mixturethereof (herein referred to as a “sulphate component”). An alkali metalor alkaline earth metal sulphate may, for example, be selected fromsodium sulphate, potassium sulphate and magnesium sulphate. The solutionmay comprise more than one of sodium sulphate, potassium sulphate andmagnesium sulphate, for example all three. Preferably, the sulphatecomponent is or includes sodium sulphate.

Preferably, the first colon cleansing solution comprises a sulphatecomponent (for example sodium sulphate) at a concentration of 2 to 20 gper litre, for example 2 to 15 g per litre, for example 5 to 15 g perlitre, for example 8 to 12 g per litre, for example 8 or 12 g per litre.For example, the first colon cleansing solution comprises 8.0 to 20 gper litre of one or more alkali metal sulphates, alkaline earth metalsulphates or a mixture thereof.

The first colon cleansing solution may comprise one or moreelectrolytes. Electrolytes include salts of sodium, potassium, calciumand magnesium, particularly sodium and potassium; and salts of chloride,iodide, bicarbonate and carbonate, particularly chloride. Preferredelectrolytes are sodium chloride and potassium chloride. In anembodiment, sodium bicarbonate is not included.

For example, the first colon cleansing solution may comprise sodiumchloride at a concentration of 0.5 to 5.0 g per litre. For example,sodium chloride may be present at a concentration of 1.0 to 4.0 g perlitre, for example 1.0 to 3.0 g per litre, for example 1.5 to 3.0 g perlitre, for example 2.0 to 3.0 g per litre.

For example, the first colon cleansing solution may comprise potassiumchloride at a concentration of 1 to 10 g per litre. For example,potassium chloride may be present at a concentration of 0.05 to 5.0 gper litre, for example 0.1 to 3.0 g per litre, for example 0.2 to 2.0 gper litre, for example 0.5 to 1.5 g per litre, for example 0.5 to 1.1 gper litre.

In an embodiment, the first colon cleansing solution comprises sodiumchloride and potassium chloride. They can be present in the amountsmentioned immediately above. For example, sodium chloride may be presentat a concentration of 1.5 to 3.0 g per litre and potassium chloride maybe present at a concentration of 0.2 to 2.0 g per litre.

The first colon cleansing solution preferably includes a flavouringagent. The first colon cleansing solution preferably includes asweetener. Flavouring agents and sweeteners may be as describedhereinabove.

In an embodiment, the first colon cleansing solution may be a solutionas commercialised under the tradename MOVIPREP®.

Accordingly, the first colon cleansing solution in a kit of theinvention comprises (or consists essentially of water and):

(i) 70 to 250 g per litre PEG having an average molecular weight of 2500to 4500 Da.

(ii) 2.0 to 20 g per litre of one or more alkali metal sulphates,alkaline earth metal sulphates or a mixture thereof

(iii) optionally one or more electrolytes;

(iv) optionally one or more flavouring agents; and

(v) optionally one or more sweeteners.

For example, the first colon cleansing solution in a kit of theinvention comprises (or consists essentially of water and):

(i) 90 to 200 g per litre PEG having an average molecular weight of 2500to 4500 Da.

(ii) 2.0 to 15 g per litre of one or more alkali metal sulphates,alkaline earth metal sulphates or a mixture thereof

(iii) 0.5 to 5.0 g per litre sodium chloride, and 0.05 to 5.0 g perlitre potassium chloride;

(iv) optionally one or more flavouring agents; and

(v) optionally one or more sweeteners.

The invention further provides, according to a third aspect, a coloncleansing solution comprising (or consisting essentially of water and):

(i) 130 to 250 g per litre PEG having an average molecular weight of2500 to 4500 Da;

(ii) 8.0 to 20 g per litre of one or more alkali metal sulphates,alkaline earth metal sulphates or a mixture thereof;

(iii 1) optionally 1.0 to 3.0 g per litre sodium chloride;

(iii 2) optionally 0.5 to 1.5 (for example 0.5 to 1.1) g per litrepotassium chloride;

(iv) optionally one or more flavouring agents; and

(v) optionally one or more sweeteners.

There is also provided a composition for the preparation of such asolution, for example by admixture with water. Preferred amounts of eachof components (i) to (v) in the solutions and compositions of the thirdaspect of the invention are as set out for the first colon cleansingsolutions and first colon cleansing compositions hereinabove andhereinbelow.

In an embodiment, the first colon cleansing solution is provided in avolume of from 300 ml up to 1200 ml. For example, the first solution mayhave a volume in a range with a lower limit of 300 ml, 400 ml, 500 ml,600 ml or 700 ml. Preferably, the lower limit is 500 ml, 600 ml or 700ml. The volume may be in a range with an upper limit of 1200 ml, 1100ml, 1000 ml, 900 ml or 800 ml. For example the volume may be in therange 400 ml to 1100 ml, for example 500 ml to 1000 ml, for example 600ml to 900 ml, for example 700 ml to 800 ml. For example, the first coloncleansing solution is provided in a volume of 750 ml. The mostappropriate volume will depend on the exact components of the solutionand the amounts in which they are present. In general, for a solution ofhigher osmotic strength, a smaller volume will be required.

The first cleansing solution may, for example, have a measuredosmolality in the range 200 to 1500 mOsmol/kg. In a preferredembodiment, it is hyper-osmotic. It may, for example have a measuredosmolality in the range 320 to 1500 mOsmol. For example, the measuredosmolality of the first cleansing solution is in the range 330 to 1200mOsmol/kg, for example 340 to 1000 mOsmol/kg, for example 350 to 800mOsmol/kg, for example 350 to 700 mOsmol/kg.

A colon cleansing solution according to the third aspect of theinvention may be used together with a solution of the first aspect ofthe invention. Alternatively, it may be used in combination with adifferent other colon cleansing solution, or used in a suitable volumeon its own. If used on its own, it may be used in a single dose or in asplit dose administration. The invention provides a method of cleansingthe colon of a subject comprising administering a solution of the thirdaspect of the invention. The solution may be administered on its own orin combination with a further, different, solution.

The invention further provides a kit comprising:

A) a first component, being a composition for the preparation of a firstcolon cleansing solution as described immediately above by admixturewith water; and

B) a second component, being a composition for the preparation of asecond colon cleansing solution by admixture with water, the secondcolon cleansing solution being a solution as described hereinabove inrelation to solutions and uses of the first aspect of the invention,

Preferably, the kit further comprises instructions for use.

For example, components A) and B) may be in dry powder, granular orother dry form. They may alternatively be in the form of concentrates orslurries. Components A) and B) may be in the same or different physicalforms. Components within A) and B) may be in the same or differentphysical forms. For example, one or both of components A) and B) are drypowders. A portion of either or each of components A) and B) may be inthe form of one or more solid tablets or capsules.

For example, a kit of the invention may comprise

A) a first component, being a composition for the preparation of a firstcolon cleansing solution comprising (or consisting essentially of waterand):

(i) 70 to 250 g per litre PEG having an average molecular weight of 2500to 4500 Da.

(ii) 2 to 20 g per litre of one or more alkali metal sulphates, alkalineearth metal sulphates or a mixture thereof

(iii) optionally one or more electrolytes;

(iv) optionally one or more flavouring agents;

(v) optionally one or more sweeteners, and

B) a second component, being a composition optionally presented in twoor more parts for the preparation of a second colon cleansing solution,comprising

a) 300 to 2000 mmol per litre ascorbate anion provided by ascorbic acid,one or more salts of ascorbic acid, or a mixture thereof; and

b) optionally 10 to 200 g per litre polyethylene glycol.

Preferably, the first solution is of different composition from thesecond. The concentrations of the components given here are theconcentrations attained when the compositions are mixed with wateraccording to the instructions provided with the kit.

The first colon cleansing solution may be used in a volume as describedhereinabove, for example 300 ml to 1200 ml, for example 600 ml to 900ml, for example 750 ml. The second colon cleansing solution may be usedin a volume as described hereinabove, for example 600 ml to 900 ml, forexample 750 ml. The second colon cleansing solution may be used in avolume as described hereinabove, for example 250 ml up to 1000 ml, forexample 400 ml to 700 ml, for example 500 ml. Instructions comprised inthe kit may instruct the user to prepare a solution by adding water tothe required volume, for example a volume as mentioned in thisparagraph.

Accordingly, a kit of the invention may comprise:

A) a first component, being a composition for the preparation of a firstcolon cleansing solution comprising (or consisting essentially of):

(i) 52.5 to 187.5 g PEG having an average molecular weight of 2500 to4500 Da.

(ii) 1.5 to 15 g of one or more alkali metal sulphates, alkaline earthmetal sulphates or a mixture thereof

(iii) optionally one or more electrolytes;

(iv) optionally one or more flavouring agents;

(v) optionally one or more sweeteners, and

B) a second component, being a composition optionally presented in twoor more parts for the preparation of a second colon cleansing solution,comprising

a) 150 to 1000 mmol ascorbate anion; and

b) optionally 5 to 100 g polyethylene glycol, the first solution beingdifferent from the second.

The first component preferably comprises 97.5 to 187.5 g of PEG, forexample 67.5 to 150 g of PEG, more preferably 75 to 150 g, for example90 to 112.5 g, for example 100 g PEG.

Preferably, the first component comprises a sulphate component (forexample sodium sulphate) in an amount of 1.5 to 11.25 g, for example3.75 to 11.25 g, for example 6 to 9 g, for example 6 or 9 g. Forexample, the first component comprises 6.0 to 15 g of one or more alkalimetal sulphates, alkaline earth metal sulphates or a mixture thereof.

Preferably, the first component comprises sodium chloride in an amountof 0.375 to 3.75 g. For example, sodium chloride may be present in anamount of 0.75 to 3.0 g, for example 0.75 to 2.25 g, for example 1.125to 2.25 g, for example 1.5 to 2.25 g.

For example, the first component comprises potassium chloride in anamount of 0.75 to 7.5 g. For example, potassium chloride may be presentin an amount of 0.0375 to 3.75 g, for example 0.075 to 2.25 g, forexample 0.15 to 1.5 g, for example 0.375 to 1.125 g, for example 0.375to 0.825 g.

In an embodiment, the first component comprises sodium chloride andpotassium chloride. They can be present in the amounts mentionedimmediately above. For example, sodium chloride may be present in anamount of 1.125 to 2.25 g and potassium chloride may be present in anamount of 0.15 to 1.5 g.

The second component of the kit of compositions of the invention ispreferably a composition for the preparation of a solution of the firstaspect of the invention as described herein above.

In an embodiment, a kit of the invention has instructions that instructthe user of the volume to which each component is to be made up withwater. For example, the specified volume of water for each solution isless than one litre. For example, the specified volume for the firstcomponent may be 300 ml to 1200 ml, for example 600 ml to 900 ml, forexample 750 ml. For example, the specified volume for the secondcomponent may be from 250 ml to 1000 ml, for example 400 ml to 700 ml,for example 500 ml. Further volumes that may be specified in theinstructions are the volumes set out hereinabove in relation to themethods of the invention.

In general, the instructions specify that the first and second solutionsare to be ingested in succession with a time interval between them. Inan embodiment, the instructions specify that the first cleansingsolution is ingested first followed, after time interval (for examplethe time between an evening and the following morning), by ingestion ofthe second cleansing solution.

It is convenient for the patient for a kit of the invention to beprovided in the form of, for example, a box. In a kit of the inventionthe first and/or second components may each contained in one or morecontainers. In particular, the second component may be contained in morethan one container. For example, if the second component comprises bothascorbic acid and PEG then the ascorbic acid and PEG may be contained inseparate containers. The other constituents of the second component (forexample one or more of sodium chloride, potassium chloride and sodiumsulphate) may be in either of the separate containers. For example, theymay be in the container containing the PEG.

If a flavouring component is present in the first or second solution,then in a kit of the invention, the flavouring component for therelevant solution may be provided in a separate container from the otherconstituents of that solution.

Examples of suitable containers include tubs, bags and sachets. Apreferred container is a sachet.

In one embodiment, a kit comprises:

-   -   A) a first sachet comprising a first composition for the        preparation of the first cleansing solution;        B1) a second sachet;        B2) a third sachet;

wherein the second and third sachets together provide a composition forthe preparation of the second cleansing solution.

For example, in a kit of the invention as mentioned immediately above:

A) the first sachet comprises polyethylene glycol and/or sodiumsulphate;

B1) the second sachet comprises one or more components selected frompolyethylene glycol, one or more alkali metal sulphates, alkaline earthmetal sulphates or a mixture thereof, electrolytes and/or one or moresalts of ascorbic acid; and

B2) the third sachet comprises ascorbic acid;

the one or more salts of ascorbic acid in the second sachet (B1) and theascorbic acid in the third sachet (B2) together providing 300 to 2000mmol per litre ascorbate anion.

For example, in a kit of the invention as mentioned immediately above:

A) the first sachet comprises:

(i) 70 to 250 g per litre PEG having an average molecular weight of 2500to 4500 Da.

(ii) 2 to 20 g per litre of one or more alkali metal sulphates, alkalineearth metal sulphates or a mixture thereof

(iii) optionally one or more electrolytes;

(iv) optionally one or more flavouring agents; and

(v) optionally one or more sweeteners,

B1) the second sachet comprises:

(i) 10 to 200 g per litre polyethylene glycol,

(ii) optionally one or more alkali metal sulphates, alkaline earth metalsulphates or a mixture thereof,

(iii) electrolytes; and

(iv) or one or more salts of ascorbic acid; and

B2) the third sachet comprises ascorbic acid, the one or more salts ofascorbic acid in the second sachet (B1) and the ascorbic acid in thethird sachet (B2) together providing 300 to 2000 mmol per litreascorbate anion.

For example, in a kit of the invention:

A) the first sachet comprises:

(i) 52.5 to 187.5 g PEG having an average molecular weight of 2500 to4500 Da.

(ii) 1.5 to 15 g of one or more alkali metal sulphates, alkaline earthmetal sulphates or a mixture thereof

(iii) optionally one or more electrolytes;

(iv) optionally one or more flavouring agents;

(v) optionally one or more sweeteners,

B1) the second sachet comprises:

(i) 5 to 100 g PEG having an average molecular weight of 2500 to 4500Da,

(ii) optionally one or more alkali metal sulphates, alkaline earth metalsulphates or a mixture thereof,

(iii) electrolytes and/or one or more salts of ascorbic acid; and

B2) the third sachet comprises ascorbic acid,

the one or more salts of ascorbic acid in the second sachet (B1) and theascorbic acid in the third sachet (B2) together providing 150 to 1000mmol ascorbate anion.

For example, in a further embodiment of a kit of the invention, ratherthan being provided within a first sachet (A) with the PEG, some or allof the sulphate(s), electrolytes, flavouring agents and sweeteners areprovided in the form of a tablet or capsule. In a further embodiment ofa kit of the invention, rather than being provided within a second orthird sachet (B1 or B2) with the PEG, ascorbic acid or ascorbatecomponent, some or all of the sulphate(s), electrolytes, flavouringagents and sweeteners are provided in the form of a tablet or capsule.

A kit may contain one treatment, for example a cleansing treatment, orseveral treatments. A treatment generally comprises one dose of thefirst cleansing solution (or components for preparing the firstcleansing solution) and one dose of the second cleansing solution (orcomponents for preparing the first cleansing solution). In a kit of theinvention, preferably the first component comprises one dose of thefirst cleansing solution, and the second component comprises one dose ofthe second cleansing solution.

A kit of the invention may be for use in a method of cleansing the coloncomprising:

-   -   the subject taking an effective amount of a first colon        cleansing solution as described herein;    -   the subject taking an effective amount of a second colon        cleansing solution as described herein.

The invention further provides a method of cleansing the coloncomprising:

-   -   the subject taking an effective amount of a first colon        cleansing solution as described herein;    -   the subject taking an effective amount of a second colon        cleansing solution as described herein.

In the method, there is typically a time interval between taking thefirst solution and taking the second solution. Generally, the timeinterval is at least 4 hours, for example 6 hours or more, for example 8hours or more. Typically, the time interval is less than 15 hours. Thetime interval between starting to take the first cleansing solution andstarting to take the second cleansing solution may be, for example, thetime between an evening and the following morning, for example 12 to 16hours, for example 14 hours. For example, the subject may sleep (forexample overnight) between taking the first and second cleansingsolutions.

In a fourth aspect, the invention provides a method of cleansing thecolon of a subject comprising:

-   -   administering to the subject an effective amount of a first        cleansing solution; and then after a time interval    -   administering to the subject an effective amount of a second        cleansing solution,

wherein the second cleansing solution is hyper-osmotic and containsascorbic acid, one or more salts of ascorbic acid, or a mixture thereof;and wherein the first cleansing solution is either substantially freefrom ascorbic acid and salts thereof, or contains ascorbic acid, one ormore salts of ascorbic acid, or a mixture thereof, in an amountproviding a lower concentration of ascorbate anion than is present inthe second cleansing solution.

For example, the invention provides a method of cleansing the colon of asubject comprising:

-   -   the subject taking an effective amount of a first cleansing        solution; and then after a time interval    -   the subject taking an effective amount of a second cleansing        solution,

wherein the second cleansing solution is hyper-osmotic and containsascorbic acid, one or more salts of ascorbic acid, or a mixture thereof;and wherein the first cleansing solution is either substantially freefrom ascorbic acid and salts thereof, or contains ascorbic acid, one ormore salts of ascorbic acid, or a mixture thereof, in an amountproviding a lower concentration of ascorbate anion than is present inthe second cleansing solution.

The amount of solution that constitutes an “effective amount” need notbe the same for the first and second solutions.

The method provides satisfactory cleansing of the colon whilst not beingwasteful of ascorbic acid component in the first cleansing solution. Inaddition, the method of the invention provides satisfactory cleansing ofthe colon with ingestion of a smaller total volume of the solutions thanin the prior art. The first cleansing solution is preferably a bowelcontent suspending agent. The second cleansing solution is a bowelmotility agent.

The invention also provides a kit comprising:

-   -   a first colon cleansing solution; and    -   a second colon cleansing solution,

wherein the second colon cleansing solution is hyper-osmotic andcontains ascorbic acid, one or more salts of ascorbic acid, or a mixturethereof; and wherein the first colon cleansing solution is eithersubstantially free from ascorbic acid and salts thereof, or containsascorbic acid, one or more salts of ascorbic acid, or a mixture thereof,in an amount providing a lower concentration of ascorbate anion in thefirst colon solution than is present in the second colon cleansingsolution.

In some embodiments of the method of the fourth aspect of the invention,the stool output immediately after the ingestion of the first solutionmay be less copious than after ingestion of the second solution. Giventhat the subject will often wish to sleep between taking the first bowelcleansing solution and the second solution, it may be advantageous incertain instances for the first cleansing solution to result in aslightly lower stool output than the second cleansing solution.

The invention also provides a kit comprising:

a) a first component, being a composition for the preparation of a firstcolon cleansing solution by admixture with a clear fluid (for examplewater); and

b) a second component, being a composition for the preparation of asecond colon cleansing solution by admixture with a clear fluid (forexample water),

and optionally instructions for use that specify the volume to whicheach component is to be made up with a clear fluid (for example water),

wherein the second colon cleansing solution, when made up to theinstructed specified volume with the clear fluid (for example water), ishyper-osmotic and contains ascorbic acid, one or more salts of ascorbicacid, or a mixture thereof; and wherein the first colon cleansingsolution is either substantially free from ascorbic acid and saltsthereof, or contains, when made up to the instructed specified volumewith the clear fluid (for example water), ascorbic acid, one or moresalts of ascorbic acid, or a mixture thereof, in an amount providing alower concentration of ascorbate anion in the first colon solution thanin the second colon cleansing solution.

In an embodiment, the invention provides a method of cleansing the colonof a subject comprising:

-   -   administering to the subject an effective amount of a first        cleansing solution; and then after a time interval    -   administering to the subject an effective amount of a second        cleansing solution, wherein the first cleansing solution        contains polyethylene glycol (PEG) and is hyper-osmotic; and        wherein the second cleansing solution contains polyethylene        glycol (PEG) and is more hyper-osmotic than the first cleansing        solution.

For example, the invention provides a method of cleansing the colon of asubject comprising:

-   -   the subject taking an effective amount of a first cleansing        solution; and then after a time interval    -   the subject taking an effective amount of a second cleansing        solution, wherein the first cleansing solution contains        polyethylene glycol (PEG) and is hyper-osmotic; and

wherein the second cleansing solution contains polyethylene glycol (PEG)and is more hyper-osmotic than the first cleansing solution.

Osmolality can be measured in various ways. In general, either freezingpoint depression or vapour-pressure alteration is used. For example, anAdvanced Instruments, Inc Model 3250 osmometer (a freezing pointdepression device) can be used. Vapour pressure measurement can also beused, for example using an ELITech Group Vapro 5600 device. Osmolalityvalues cited herein are preferably taken to be values measured using afreezing point depression osmometer, for example using an AdvancedInstruments, Inc Model 3250 osmometer following standard operatingprocedure.

The amount of solution that constitutes an “effective amount” need notbe the same for the first and second solutions.

The method of the invention provides satisfactory cleansing of the colonwith ingestion of a smaller total volume of the solutions than in theprior art. The reduced volume requirement helps to improve patientcompliance.

For example, the second cleansing solution may comprise ascorbic acid,one or more salts of ascorbic acid, or a mixture thereof. In solution,ascorbic acid and salts thereof provide ascorbate anion.

Depending on the pH of the solution, some ascorbate anion is protonatedand thus exists as free ascorbic acid. At the pH of solutions that wouldtypically be administered, only a very minor proportion of ascorbate isprotonated. In calculations of concentrations of “ascorbate anion”herein, the concentration of “ascorbate anion” is taken as the totalconcentration of all ascorbate anion present, including the proportionthat is protonated. Ascorbic acid or salts thereof, contribute to theosmotic load, along with other solutes. In one embodiment, the firstcleansing solution does not contain ascorbic acid or a salt thereof.Alternatively, the first solution may contain ascorbic acid, one or moresalts of ascorbic acid, or a mixture thereof. Typically, if the firstsolution contains ascorbic acid, one or more salts of ascorbic acid, ora mixture thereof, it contains them in an amount providing a lowerconcentration of ascorbate anion than is present in the second cleansingsolution.

The invention also provides a kit comprising:

-   -   a first colon cleansing solution; and    -   a second colon cleansing solution,

wherein the first cleansing solution contains polyethylene glycol (PEG)and is hyper-osmotic; and wherein the second cleansing solution containspolyethylene glycol (PEG) and is more hyper-osmotic than the firstcleansing solution.

The invention also provides a kit comprising:

a) a first component, being a composition for the preparation of a firstcolon cleansing solution by admixture with a clear fluid (for examplewater); and

b) a second component, being a composition for the preparation of asecond colon cleansing solution by admixture with a clear fluid (forexample water),

and instructions for use that specify the volume to which each componentis to be made up with a clear fluid (for example water),

wherein the first cleansing solution contains polyethylene glycol (PEG)and, when made up to the instructed specified volume with the clearfluid (for example water), is hyper-osmotic; and wherein the secondcleansing solution contains polyethylene glycol (PEG) and, when made upto the instructed specified volume with the clear fluid (for examplewater), is more hyper-osmotic than the first cleansing solution.

For example, components a) and b) may be in dry powder, granular orother dry form. They may alternatively be in the form of concentrates orslurries. Components a) and b) may be in the same or different physicalforms. Components within a) and b) may be in the same or differentphysical forms. For example, one or both of components a) and b) are drypowders.

In an embodiment, the invention provides a method of cleansing the colonof a subject comprising:

-   -   administering to the subject an effective amount of a first        cleansing solution; and then after a time interval    -   administering to the subject an effective amount of a second        cleansing solution,

wherein the first cleansing solution and the second cleansing solutionare different, and wherein the first cleansing solution contains analkali metal sulphate, an alkaline earth metal sulphate or a mixturethereof; and the second cleansing solution contains ascorbic acid, oneor more salts of ascorbic acid, or a mixture thereof.

The amount of solution that constitutes an “effective amount” need notbe the same for the first and second solutions.

The first cleansing solution may contain polyethylene glycol (PEG). Whenmade up to the instructed specified volume with water, it is preferablyhyper-osmotic. The second cleansing solution may contain polyethyleneglycol (PEG). When made up to the instructed specified volume withwater, it may be hyper-osmotic, preferably more hyper-osmotic than thefirst cleansing solution.

Typically, if the first solution contains ascorbic acid, one or moresalts of ascorbic acid, or a mixture thereof, it contains them in anamount providing a lower concentration of ascorbate anion than ispresent in the second cleansing solution. In an embodiment, the firstcleansing solution does not contain ascorbic acid, one or more salts ofascorbic acid, or a mixture thereof. Typically, if the second solutioncontains an alkali metal sulphate, an alkaline earth metal sulphate or amixture thereof it contains them in an amount providing a lowerconcentration of sulphate anion than is present in the first cleansingsolution. In an embodiment, the second cleansing solution does notcontain an alkali metal sulphate, an alkaline earth metal sulphate or amixture thereof.

For example, the invention provides a method of cleansing the colon of asubject comprising:

-   -   the subject taking an effective amount of a first cleansing        solution; and then after a time interval    -   the subject taking an effective amount of a second cleansing        solution,

wherein the first cleansing solution and the second cleansing solutionare different, and wherein the first cleansing solution contains analkali metal sulphate, an alkaline earth metal sulphate or a mixturethereof; and the second cleansing solution contains ascorbic acid, oneor more salts of ascorbic acid, or a mixture thereof.

The amount of solution that constitutes an “effective amount” need notbe the same for the first and second solutions.

The method of the invention provides satisfactory cleansing of the colonwith ingestion of a smaller total volume of the solutions than in theprior art. The reduced volume requirement helps to improve patientcompliance.

For example, the second cleansing solution may comprise ascorbic acid,one or more salts of ascorbic acid, or a mixture thereof. In solution,ascorbic acid and salts thereof provide ascorbate anion. Ascorbic acidor salts thereof, contribute to the osmotic load, along with othersolutes. In one embodiment, the first cleansing solution does notcontain ascorbic acid or a salt thereof. Alternatively, the firstsolution may contain ascorbic acid, one or more salts of ascorbic acid,or a mixture thereof. Typically, if the first solution contains ascorbicacid, one or more salts of ascorbic acid, or a mixture thereof, itcontains them in an amount providing a lower concentration of ascorbateanion than is present in the second solution.

The invention also provides a kit comprising:

-   -   a first colon cleansing solution; and    -   a second colon cleansing solution,

wherein the first cleansing solution and the second cleansing solutionare different, and wherein the first cleansing solution contains analkali metal sulphate, an alkaline earth metal sulphate or a mixturethereof; and the second cleansing solution contains ascorbic acid, oneor more salts of ascorbic acid, or a mixture thereof.

The first cleansing solution may contain polyethylene glycol (PEG). Whenmade up to the instructed specified volume with water, it is preferablyhyper-osmotic. The second cleansing solution may contain polyethyleneglycol (PEG). When made up to the instructed specified volume withwater, it may be hyper-osmotic, preferably more hyper-osmotic than thefirst cleansing solution.

The invention also provides a kit comprising:

a) a first component, being a composition for the preparation of a firstcolon cleansing solution by admixture with a clear fluid (for examplewater); and

b) a second component, being a composition for the preparation of asecond colon cleansing solution by admixture with a clear fluid (forexample water),

and instructions for use that specify the volume to which each componentis to be made up with a clear fluid (for example water),

wherein the first cleansing solution and the second cleansing solutionare different, and wherein the first cleansing solution contains analkali metal sulphate, an alkaline earth metal sulphate or a mixturethereof; and the second cleansing solution contains ascorbic acid, oneor more salts of ascorbic acid, or a mixture thereof.

For example, components a) and b) may be in dry powder, granular orother dry form. They may alternatively be in the form of concentrates orslurries. Components a) and b) may be in the same or different physicalforms. Components within a) and b) may be in the same or differentphysical forms. For example, one or both of components a) and b) are drypowders.

In a further embodiment, the invention provides a method of cleansingthe colon of a subject comprising:

-   -   administering to the subject an effective amount of a first        cleansing solution; and then after a time interval    -   administering to the subject an effective amount of a second        cleansing solution,

wherein the first cleansing solution and the second cleansing solutionare different and, together, comprise the components:

-   -   a) 80 to 250 g of a polyethylene glycol;    -   b) 10 to 150 g of ascorbic acid, one or more salts of ascorbic        acid or a mixture of ascorbic acid and one or more salts of        ascorbic acid (the “ascorbate component”);    -   c) 1 to 15 g of an alkali metal or alkaline earth metal sulphate        or a mixture of alkali metal or alkaline earth metal sulphates        (the “sulphate component”);    -   d) 1 to 15 g of electrolytes;    -   e) optionally one or more sweeteners, and    -   f) optionally one or more flavourings

wherein the sulphate component is in the first cleansing solution andthe ascorbate component is in the second cleansing solution.

The amount of solution that constitutes an “effective amount” need notbe the same for the first and second solutions.

The invention further provides a kit comprising two or more compositionsfor separate admixture with a clear fluid (for example water) whereinthe compositions together comprise the components:

-   -   a) 80 to 250 g of a polyethylene glycol;    -   b) 10 to 150 g of ascorbic acid, one or more salts of ascorbic        acid or a mixture of ascorbic acid and one or more salts of        ascorbic acid (the “ascorbate component”);    -   c) 1 to 15 g of an alkali metal or alkaline earth metal sulphate        or a mixture of alkali metal or alkaline earth metal sulphates        (the “sulphate component”);    -   d) 1 to 15 g of electrolytes;    -   e) optionally one or more sweeteners;    -   f) optionally one or more flavourings

wherein the components are arranged such that the sulphate component isin a first dry composition and the ascorbate component is in second drycomposition.

For example, the components of the two or more compositions may be indry powder, granular or other dry form. They may alternatively be in theform of concentrates or slurries. The two or more compositions may be inthe same or different physical forms. Components within each of the twoor more compositions may be in the same or different physical forms. Forexample, one or both of the compositions is a dry powder. The clearfluid may be the same or different for the two or more compositions.

The invention further provides a kit comprising two or more solutionswherein the solutions together comprise the components:

-   -   a) 80 to 250 g of a polyethylene glycol;    -   b) 10 to 150 g of ascorbic acid, one or more salts of ascorbic        acid or a mixture of ascorbic acid and one or more salts of        ascorbic acid (the “ascorbate component”);    -   c) 1 to 15 g of an alkali metal or alkaline earth metal sulphate        or a mixture of alkali metal or alkaline earth metal sulphates        (the “sulphate component”);    -   d) 1 to 15 g of electrolytes;    -   e) optionally one or more sweeteners;    -   f) optionally one or more flavourings

wherein the components are arranged such that the sulphate component isin a first solution and the ascorbate component is in second solution.

For example, each of the first and second compositions (or solutions)may contain some of the electrolytes of component d). For example, eachof the first and second compositions (or solutions) may contain some ofthe polyethylene glycol of component a). Alternatively, the polyethyleneglycol of component a) may be contained only in the first composition(or solution). For example, each of the first and second compositions(or solutions) may contain some of the sweetener of component e). Forexample, each of the first and second compositions (or solutions) maycontain some of the flavouring of component f). The first composition(or solution) may contain more of component e) or f) than the secondcomposition (or solution).

In an alternative embodiment, a method, solution or kit is providedwherein the first cleansing solution and the second cleansing solutionhave different compositions and, together, comprise the components:

-   -   a) 80 to 250 g of a polyethylene glycol;    -   b) 10 to 150 g of ascorbic acid, one or more salts of ascorbic        acid or a mixture of ascorbic acid and one or more salts of        ascorbic acid (the “ascorbate component”);    -   c) 1 to 15 g of an alkali metal or alkaline earth metal sulphate        or a mixture of alkali metal or alkaline earth metal sulphates        (the “sulphate component”);    -   d) 1 to 15 g of electrolytes;    -   e) optionally one or more sweeteners, and    -   f) optionally one or more flavourings;

wherein the pair of solutions is not a combination in which:

the first solution contains 100 g PEG3350, 3 g Na₂SO₄, 1.4 g NaCl and0.3 g KCl; or the first solution contains 100 g PEG3350, 6 g Na₂SO₄, 1.6g NaCl and 0.7 g KCl; or the first solution contains 100 g PEG3350, 9 gNa₂SO₄, 2.0 g NaCl and 1.0 g KCl; and the second solution contains 40 gPEG3350, 3.5 g NaCl, 2.2 g KCl and 56.6 g sodium ascorbate; or thesecond solution contains 20 g PEG3350, 2.7 g NaCl, 1.3 g KCl, 33.9 gsodium ascorbate and 20.1 g ascorbic acid; or the second solutioncontains 40 g PEG3350, 2.8 g NaCl, 3.1 g KCl 33.9 g sodium ascorbate and20.1 g ascorbic acid; or the second solution contains 40 g PEG3350, 6 gNa₂SO₄, 2.8 g NaCl, 2.0 g KCl and 33.9 g sodium ascorbate; or the secondsolution contains 40 g PEG3350, 3.1 g NaCl, 1.3 g KCl, 33.9 g sodiumascorbate and 21.4 g magnesium ascorbate.

The combined volume of the first and second cleansing solutions ispreferably less than 2 litres. Preferably, it is 1750 ml or less, forexample 1500 ml or less, for example 1250 ml or less. For most adultsubjects, a combined volume of more than 500 ml is used, for examplemore than 750 ml. For example, a combined volume of from 500 ml to 1750ml is used, for example from 750 ml to 1500 ml, for example from 1000 mlto 1500 ml, for example 1250 ml. For example the first cleansingsolution may have a volume of 750 ml and the second cleansing solutionmay have a volume of 500 ml.

In an embodiment, the subject may take some additional clear fluid aftertaking the first cleansing solution but before taking the secondcleansing solution; and/or after taking the second cleansing solution.In an embodiment, the total amount of additional clear fluid that thesubject takes is in the range 1000 ml to 2500 ml, for example 1750 ml.

A clear fluid for taking as the additional clear fluid, or for use asthe clear fluid when making up a solution, may be any fluid that allowsinspection of colonic output. The clear fluid should also not impedeinspection of the colon during the colonoscopy. Typically the clearfluid is a water-based beverage, including, for example, water,lemonade, cola drinks, cordial drinks, clear fruit juices and even clearalcohol-containing beverages, for example beer. It is desirable that theclear fluid does not contain substantial amounts of or essentially anydietary fibre, as such fibre interferes with the cleansing of the colonaccording to the present invention. Accordingly, fruit juices, forexample orange juice and kiwi juice, and fruit “squashes” should bestrained before use. Clear fruit cordials, for example, lime cordial,are generally suitable. In view of the desirability of avoiding drinkscontaining glucose, so as to reduce the risk of explosive concentrationsof hydrogen or methane building up in the gut, “diet” drinks containingno or low sugar are especially suitable, for example liquid drinks fordiabetics, diet Coke®, diet lemonade, dietary carbonated drinks ordietary cordials.

The time interval in the method of the invention is generally at least 4hours, for example 6 hours or more, for example 8 hours or more.Typically, the time interval is less than 15 hours. The time intervalbetween starting to take the first cleansing solution and starting totake the second cleansing solutions may be, for example, the timebetween an evening and the following morning, for example 12 to 16hours, for example 14 hours. For example, the subject may sleep (forexample overnight) between taking the first and second cleansingsolutions. The time between finishing taking the first solution andstarting to take the second solution is somewhat less, and that dependson the time the subject takes to complete the first solution. Typically,the first solution is taken over a period of up to two hours, forexample an hour. Therefore the time between finishing taking the firstsolution and starting to take the second solution is for example 11 to15 hours, for example 13 hours.

During the time interval between the administration of the firstcleansing solution and the second cleansing solution, the subject mayadditionally take a stimulant laxative (also known as a prokineticagent). A stimulant laxative can assist in bringing about goodcleansing. Examples of stimulant laxatives include contact laxatives,for example bisacodyl, castor oil or senna. Examples of stimulantlaxatives also include additional osmotic agents for example magnesiumsalts, for example magnesium citrate. If a stimulant laxatives isincluded in the regimen, the length of the time interval can beshortened. For example, it may be 1 to 15 hours, for example 1 to 12hours, for example 2 to 10 hours.

During the time interval between the administration of the firstcleansing solution and the second cleansing solution, it is very likelythat the subject will experience a bowel movement.

Advantageously, the subject waits until the bowel movement has occurredbefore taking the second cleansing solution.

The second cleansing solution, and optionally the first cleansingsolution contains ascorbic acid, one or more salts thereof, or a mixturethereof. For convenience, they will be referred to herein as the“ascorbate component”.

Suitable salts of the ascorbic acid include alkali metal and alkalineearth metal salts. For example, preferred salts of ascorbic acid includesodium ascorbate and magnesium ascorbate. In an embodiment, one ofsodium ascorbate and magnesium ascorbate is present.

In one embodiment, the ascorbate component comprises both ascorbic acidand one or more salts of ascorbic acid. For example, the ascorbatecomponent may comprise ascorbic acid and sodium ascorbate. For example,the ascorbate component may comprise ascorbic acid and magnesiumascorbate.

In an embodiment, a mixture of salts of ascorbic acid is used. Forexample, both sodium ascorbate and magnesium ascorbate may be present.They may be present with ascorbic acid, or without ascorbic acid.

The second cleansing solution contains a higher concentration ofascorbate anion than is present in the first cleansing solution. Forexample, the second cleansing solution contains twice the concentrationof the ascorbate anion than the first cleansing solution or more. Forexample, the second solution contains three times or more, four times ormore, or five times or more the concentration of the ascorbate anionthan the first cleansing solution. For example, the second cleansingsolution contains a concentration of the ascorbate anion that is atleast 50 mmol per litre greater than that of the first cleansingsolution. That is to say that the second solution contains aconcentration of ascorbate anion that is at least 50 mmol per litregreater than that of the first solution. For example, the secondsolution contains a concentration of the ascorbate anion that is greaterby at least 100 mmol per litre, for example at least 200 mmol per litre,at least 300 mmol per litre.

For example, the first cleansing solution may be substantially free froman ascorbate component.

For example, the second cleansing solution may comprise:

-   -   56.6 g sodium ascorbate, or    -   33.9 g sodium ascorbate and 20.1 g ascorbic acid, or    -   33.9 g sodium ascorbate, or    -   33.9 g sodium ascorbate and 21.4 g magnesium ascorbate.

The second cleansing solution may further comprise polyethylene glycol.The polyethylene glycol (PEG) may, for example, have an averagemolecular weight of 2500 to 4500 Da, for example 3000 to 4000 Da. Forexample, the PEG may be PEG 3350 or PEG 4000 as defined in nationalpharmacopeias. Further examples of suitable PEGs recognized in somenational pharmacopeias include Macrogols, for example Macrogol 4000.

For example, the second cleansing solution may comprise 20 g or 40 g PEG3350. For example, the second cleansing solution may have a volume of500 ml.

The first cleansing solution may comprise polyethylene glycol and/or analkali metal sulphate, an alkaline earth metal sulphate, or a mixturethereof.

The polyethylene glycol (PEG) in the first cleansing solution may be asdescribed immediately above for the second cleansing solution. The PEGin the first cleansing solution can be a different PEG from the PEG inthe second cleansing solution. For example, one PEG may be PEG3350 andthe other PEG may be PEG4000. For example, the first cleansing solutionmay comprise 100 g PEG 3350. For example, the first cleansing solutionmay have a volume of 750 ml.

The first cleansing solution preferably comprises an alkali metalsulphate, an alkaline earth metal sulphate or a mixture thereof. Analkali metal or alkaline earth metal sulphate may, for example, beselected from sodium sulphate, potassium sulphate and magnesiumsulphate. The solution may comprise more than one of sodium sulphate,potassium sulphate and magnesium sulphate, for example all three.Preferably, the alkali metal sulphate, an alkaline earth metal sulphateor the mixture thereof is or includes sodium sulphate. Preferably, analkali metal sulphate or alkaline earth metal sulphate (for examplesodium sulphate) is anhydrous.

For example, the first cleansing solution may have a volume of 750 mland comprise 3 g, 6 g or 9 g of sodium sulphate.

The first and/or second cleansing solution(s) may further comprise oneor more of:

a) one or more electrolytes;

b) one or more flavouring agents;

c) one or more sweeteners.

Electrolytes include salts of sodium, potassium, calcium and magnesium,particularly sodium and potassium; and salts of chloride, iodide,bicarbonate and carbonate, particularly chloride. Preferred electrolytesare sodium chloride and potassium chloride. In an embodiment, the firstand/or second solution is substantially free from sodium bicarbonate.

For example, the first cleansing solution may have a volume of 750 mland comprise 1.4 g sodium chloride and 0.3 g potassium chloride; or 1.6g sodium chloride and 0.7 g potassium chloride; or 2.0 g sodium chlorideand 1.0 g potassium chloride.

For example, the second cleansing solution may have a volume of 500 mland comprise 3.5 g sodium chloride and 2.2 g potassium chloride; or 2.7g sodium chloride and 1.3 g potassium chloride; or 2.8 g sodium chlorideand 1.3 g potassium chloride; or 2.8 g sodium chloride and 2.0 gpotassium chloride; or 3.1 g sodium chloride and 1.3 g potassiumchloride. For example the second cleansing solution is substantiallyfree from sodium bicarbonate.

In the solutions of the invention described herein, the quantities ofthe individual components recited do not include any solutes that may bepresent in the water used to prepare the solutions, for example, in hardwater areas there may be significant amounts of Ca²⁺ and Mg²⁺carbonates, bicarbonates or sulphates present in tap water.

The first and/or second cleansing solution(s) preferably include aflavouring agent. Flavouring for use in compositions of the inventionshould preferably mask saltiness, be relatively sweet but notexcessively so, and be stable in the composition. Flavouring makes thesolutions more palatable and thus aids patient compliance. Preferredflavourings include lemon e.g. Ungerer Lemon (available from UngererLimited, Sealand Road, Chester, England CH1 4LP) strawberry e.g. UngererStrawberry, grapefruit e.g. Ungerer Grapefruit flavouring powder,blackcurrant e.g. Ungerer Blackcurrant, pineapple e.g. IFF(International Flavours and Fragrances) Pineapple flavouring powder andvanilla/lemon and lime e.g. IFF Vanilla and Givaudin Roure Lemon andLime Flav-o-lok. Those and further suitable flavourings are availablefrom International Flavours and Fragrances Inc. (Duddery Hill,Haverhill, Suffolk, CB9 8LG, England), Ungerer & Company (Sealand Road,Chester, England CH1 4LP) or Firmenich (Firmenich UK Ltd., Hayes Road,Southall, Middlesex UB2 5NN). More preferred flavourings are lemon,kiwi, strawberry, grapefruit and orange. The most preferred flavouringsare lemon flavour and orange flavour.

The first and/or second cleansing solution(s) preferably include asweetener. Sugar-based sweeteners are generally not suited for coloncleansing compositions because the delivery of unabsorbed sugars to thecolon provides a substrate for bacteria. Such sugars may be metabolisedby the bacteria to form explosive gases such as hydrogen and methane.The presence of explosive gases in the colon can be highly dangerouswhen electrical apparatus is to be used during colonoscopy or otherprocedures. Preferred sweeteners include aspartame, acesulfame potassium(acesulfame K), sucralose and saccharine, and/or combinations thereof.For example, compositions of the invention may comprise one or both ofaspartame and acesulfame potassium (acesulfame K). For example,compositions of the invention may comprise one or both of sucralose andacesulfame potassium (acesulfame K). Alternatively, compositions of theinvention can be substantially free from added sweeteners, for exampleto minimize the number of different components in the compositions.Citric acid may also be present as a taste enhancer.

As mentioned above, in the various embodiments of the fourth aspect ofthe invention, the first or second solution may include electrolytes. Inan alternative embodiment, some or all of the electrolytes may beprovided in a tablet or capsule for co-administration with therespective solution. A tablet or capsule may include sweetener orflavouring.

The first cleansing solution may, for example, have a measuredosmolality in the range 200 to 1500 mOsmol/kg. In a preferredembodiment, it is hyper-osmotic (that is to say that it has a higherosmotic strength than blood in the human body). It may, for example,have a measured osmolality in the range 320 to 1500 mOsmol/kg. Forexample, the measured osmolality of the first cleansing solution is inthe range 330 to 1200 mOsmol/kg, for example 340 to 1000 mOsmol/kg, forexample 350 to 800 mOsmol/kg, for example 350 to 700 mOsmol/kg.

The second cleansing solution is hyper-osmotic. That is to say that ithas a higher osmotic strength than blood in the human body. It may, forexample, have a measured osmolality in the range 500 to 2000 mOsmol/kg.For example, the osmolality may be in the range 700 to 1800 mOsmol/kg,for example 800 to 1700 mOsmol/kg, for example 900 to 1600 mOsmol/kg,for example 900 to 1300 mOsmol/kg, for example 1000 to 1300 mOsmol/kg.

In an embodiment, the second cleansing solution is more hyper-osmoticthan the first cleansing solution. For example, the ratio between theosmolality of the second cleansing solution and the osmolality of thefirst cleansing solution is from 6:1 to 1.3:1. For example, the ratio isfrom 5:1 to 1.3:1, for example from 3.5:1 to 1.5:1, for example from2.5:1 to 1.6:1.

Osmolality can be measured in various ways. In general, either freezingpoint depression or vapour-pressure alteration is used. For example, anAdvanced Instruments, Inc Model 3250 osmometer (a freezing pointdepression device) can be used. Vapour pressure measurement can also beused, for example using an ELITech Group Vapro 5600 device. Osmolalityvalues cited herein are preferably taken to be values measured using afreezing point depression osmometer, for example using an AdvancedInstruments, Inc Model 3250 osmometer following standard operatingprocedure.

In general it is not necessary for the solutions to includepreservatives or anti-oxidants. Nevertheless, low levels ofanti-oxidants or preservatives may be used if required.

The method of the invention may be used to cleanse the colon prior tocarrying out a diagnostic, therapeutic or surgical procedure on thecolon, rectum or anus or elsewhere in the abdomen in a subject. Thesubject is most preferably a human. The diagnostic or surgical proceduremay, for example, be colonoscopy, barium enema examination,sigmoidoscopy (for example flexible sigmoidoscopy) or colon surgery. Themethod of the invention may be a method of cleansing the colon prior toa surgical or diagnostic procedure comprising administering the firstsolution and then after a time interval administering the secondsolution prior to said procedure.

The solutions, compositions and kits described herein also find use inthe treatment of constipation and faecal impaction. The invention thusprovides solutions, compositions and kits as described herein for use inthe treatment of constipation or faecal impaction. The invention alsoprovides methods of treating constipation or faecal impaction comprisingadministration of solutions as described herein.

The invention further provides a kit comprising:

-   -   a first colon cleansing solution; and    -   a second colon cleansing solution,

wherein the second colon cleansing solution is hyper-osmotic andcontains ascorbic acid, one or more salts of ascorbic acid, or a mixturethereof; and wherein the first colon cleansing solution is eithersubstantially free from ascorbic acid and salts thereof, or containsascorbic acid, one or more salts of ascorbic acid, or a mixture thereof,in an amount providing a lower concentration of ascorbate anion in thefirst colon solution than is present in the second colon cleansingsolution.

A kit may further comprise instructions for use. The use may be asdescribed above in relation to methods of the invention.

In a kit of the invention, the components of the first and secondsolutions are as described hereinabove in relation to the methods of theinvention.

The invention further provides a first solution, and a second solution,for use in a method of cleansing the colon of a subject comprising:

-   -   the subject taking an effective amount of a first cleansing        solution; and then after a time interval    -   the subject taking an effective amount of a second cleansing        solution,

wherein the second cleansing solution is hyper-osmotic and containsascorbic acid, one or more salts of ascorbic acid, or a mixture thereof;and wherein the first cleansing solution is either substantially freefrom ascorbic acid and salts thereof, or contains ascorbic acid, one ormore salts of ascorbic acid, or a mixture thereof, in an amountproviding a lower concentration of ascorbate anion than is present inthe second cleansing solution.

The invention further provides a solution that is hyper-osmotic andcontains ascorbic acid, one or more salts of ascorbic acid, or a mixturethereof, for use in a method of cleansing the colon of a subjectcomprising:

-   -   the subject taking an effective amount of a first cleansing        solution; and then after a time interval    -   the subject taking an effective amount of a second cleansing        solution,

wherein the second cleansing solution is hyper-osmotic and containsascorbic acid, one or more salts of ascorbic acid, or a mixture thereof;and wherein the first cleansing solution is either substantially freefrom ascorbic acid and salts thereof, or contains ascorbic acid, one ormore salts of ascorbic acid, or a mixture thereof, in an amountproviding a lower concentration of ascorbate anion than is present inthe second cleansing solution.

The solutions for use in a method of cleansing the colon in accordancewith the invention are as described hereinabove in relation to themethods of the invention.

In an embodiment, the invention provides a kit comprising:

a) a first component, being a composition for the preparation of a firstcolon cleansing solution by admixture with a clear fluid (for examplewater); and

b) a second component, being a composition for the preparation of asecond colon cleansing solution by admixture with a clear fluid (forexample water),

and instructions for use that specify the volume to which each componentis to be made up with water,

wherein the second colon cleansing solution, when made up to theinstructed specified volume with the clear fluid (for example water), ishyper-osmotic and contains ascorbic acid, one or more salts of ascorbicacid, or a mixture thereof; and wherein the first colon cleansingsolution is either substantially free from ascorbic acid and saltsthereof, or contains, when made up to the instructed specified volumewith the clear fluid (for example water), ascorbic acid, one or moresalts of ascorbic acid, or a mixture thereof, in an amount providing alower concentration of ascorbate anion in the first colon solution thanin the second colon cleansing solution.

The constituent parts of the composition for the preparation of a firstcleansing solution by admixture with water are, for example, asdescribed hereinabove in relation to the first solution in the methodsof the invention. The constituent parts of the composition for thepreparation of a second cleansing solution by admixture with water are,for example, as described hereinabove in relation to the second solutionin the methods of the invention.

For example, components a) and b) may be in dry powder granular or otherdry form. They may alternatively be in the form of concentrates orslurries. Components a) and b) may be in the same or different physicalforms. Components within a) and b) may be in the same or differentphysical forms. For example, one or both of components a) and b) are drypowders.

In an embodiment, a kit of the invention has instructions in which thespecified volume of water for each solution is less than one litre. Forexample, the combination of the specified volumes of the first andsecond cleansing solutions is preferably less than 2 litres. Preferably,it is 1750 ml or less, for example 1500 ml or less, for example 1250 mlor less. For most adult subjects, a combined volume of more than 500 mlis used, for example more than 750 ml. For example, a combined volume offrom 500 ml to 1750 ml is used, for example from 750 ml to 1500 ml, forexample from 1000 ml to 1500 ml, for example 1250 ml. For example avolume of 750 ml may be specified for the first cleansing solution and avolume of 500 ml may be specified for the second cleansing solution. Theinstructions may specify that a cleansing solution is consumedimmediately after it has been prepared. They may specify that thecleansing solution is prepared and then stored in a fridge beforeconsumption at a slightly later time.

In general, the instructions specify that the first and second solutionsare to be ingested in succession with a time interval between them. Inan embodiment, the instructions specify that the first cleansingsolution is ingested first followed, after a time interval (for examplethe time between an evening and the following morning) by ingestion ofthe second cleansing solution. The time interval is preferably asdescribed above in relation to the methods of the invention.

It is convenient for the patient for a kit of the invention to beprovided in the form of, for example, a box. In a kit of the inventionthe first and/or second components may each be contained in one or morecontainers. In particular, the second component may be contained in morethan one container. For example, if the second component comprises bothascorbic acid and PEG then the ascorbic acid and PEG may be contained inseparate containers. The other constituents of the second component (forexample one or more of sodium chloride, potassium chloride and sodiumsulphate) may be in either of the separate containers. For example, theymay be in the container containing the PEG.

If a flavouring component and/or sweetening component is present in thefirst or second solution, then in a kit of the invention, the flavouringand/or sweetener component for the relevant solution may be provided ina separate container from the other constituents of that solution.Alternatively, the flavouring and/or sweetener may be in the samecontainer as one or more other components. For example, any flavouringor sweetener may be in the same container as PEG.

Examples of suitable containers include tubs, bags and sachets. Apreferred container is a sachet.

In one embodiment, a kit comprises:

a) a first sachet comprising a first composition for the preparation ofa first cleansing solution;

b) a second sachet;

c) a third sachet;

and instructions for use

wherein the second and third sachets together provide a composition forthe preparation of a second colon cleansing solution, and

wherein the first and second cleansing solutions are as describedherein-above.

For example, in a kit of the invention as mentioned immediately above:

a) the first sachet comprises polyethylene glycol and/or sodiumsulphate, optional flavouring and/or optional sweetener;

b) the second sachet comprises polyethylene glycol, and optionallyfurther components including one or more selected from an alkali metalsulphate, an alkaline earth metal sulphate, or a mixture thereof,electrolytes, one or more salts of ascorbic acid, flavouring andsweetener; andc) the third sachet comprises ascorbic acid and optionally one or moresalts of ascorbic acid.

A kit may contain one treatment, for example a cleansing treatment, orseveral treatments. A treatment generally comprises one dose of thefirst cleansing solution and one dose of the second cleansing solution.In a kit of the invention, preferably the first component comprises onedose of the first cleansing solution, and the second component comprisesone dose of the second cleansing solution.

For example, in a kit of the invention:

a) the first sachet comprises 100 g PEG 3350, 3 g sodium sulphate, 1.4 gsodium chloride and 0.3 g potassium chloride; or 100 g PEG 3350, 6 gsodium sulphate, 1.6 g sodium chloride and 0.7 g potassium chloride; or1.00 g PEG 3350, 9 g sodium sulphate, 2.0 g sodium chloride and 1.0 gpotassium chloride; and optional flavouring and/or optional sweetener;b) the second sachet comprises (i) 40 g PEG 3350, 3.5 g sodium chlorideand 2.2 g potassium chloride; or (ii) 20 g PEG 3350 2.7 g sodiumchloride and 1.3 g potassium chloride; or (iii) 40 g PEG 3350, 2.8 gsodium chloride and 1.3 g potassium chloride; or (iv) 40 g PEG 3350, 2.8g sodium chloride and 2.0 g potassium chloride; or (v) 40 g PEG 3350,3.1 g sodium chloride and 1.3 g potassium chloride; and optionalflavouring and/or optional sweetener; andc) the third sachet comprises for use with the respectively numberedsecond sachet (i) 56.6 g sodium ascorbate; or (ii) and (iii) 33.9 gsodium ascorbate and 20.1 g ascorbic acid; or (iv) 33.9 g sodiumascorbate; or (v) 33.9 g sodium ascorbate and 21.4 g magnesiumascorbate.

In such kits, the contents of the sachets may consist essentially of therecited components.

As mentioned above, some or all of the electrolytes may be provided in atablet or capsule for co-administration with the respective solution.Accordingly, in a kit as described immediately above, some or all of thesodium chloride and potassium chloride in the first or second sachet mayinstead be provided in a tablet or capsule.

In an embodiment, the kit can be provided to the subject with aplurality of flavouring agents (each optionally with one or moresweeteners), each separately packaged. The subject can then select apreferred flavouring (or flavouring and sweetener combination) accordingto his or her taste. The subject also has the choice of not using anyflavouring or sweetener at all.

Unless stated otherwise, a composition that is described herein ascomprising a recited set of components is to be taken as comprising thecomponents in admixture. If a composition is said to be presented in twoor more parts, then the components need not all be in physicaladmixture. Typically, they are provided together in the article providedto the subject.

To summarise, the invention provides a colon cleansing solutioncomprising (or consisting essentially of):

a) 300 to 2000 mmol per litre ascorbate anion (provided by ascorbicacid, one or more salts of ascorbic acid selected from sodium ascorbate,potassium ascorbate, magnesium ascorbate and calcium ascorbate, or amixture thereof); preferably 350 to 800 mmol;

b) 10 to 200 g per litre PEG having an average molecular weight of 3000to 4000 Da; preferably 20 to 100 g per litre

c) optionally sodium chloride (for example 3 to 7 g per litre) andpotassium chloride (for example 2 to 5 g per litre);

d) optionally sodium sulphate (if present, for example 2 to 20 g perlitre);

e) optionally one or more flavouring agents; and

f) optionally one or more sweeteners.

The invention also provides a composition (optionally presented in twoor more parts) for admixture with water to provide a solution of theinvention. The electrolytes may optionally be provided as a tablet or acapsule to be co-administered with the solution.

The invention also provides a method of cleansing the colon of a subjectcomprising:

-   -   administering to the subject an effective amount of a first        cleansing solution; and then after a time interval    -   administering to the subject an effective amount of a second        cleansing solution,

wherein the second cleansing solution is hyper-osmotic and containsascorbic acid, one or more salts of ascorbic acid, or a mixture thereof(for example ascorbic acid and sodium ascorbate, for example sodiumascorbate); and wherein the first cleansing solution is eithersubstantially free from ascorbic acid and salts thereof, or containsascorbic acid, one or more salts of ascorbic acid, or a mixture thereof,in an amount providing a lower concentration of ascorbate anion than ispresent in the second cleansing solution. The second cleansing solutionmay comprise PEG and electrolytes (for example sodium chloride andpotassium chloride). The first solution may comprise PEG; it maycomprise an alkali metal or alkaline earth metal sulphate (for examplesodium sulphate); it may comprise electrolytes (for example sodiumchloride and potassium chloride). There are also provided kitscomprising a first and a second solution according to the invention, andkits comprising compositions for preparing the first and secondsolutions.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the mean concentration of ascorbic acid(μg/ml) in plasma over time in subjects receiving the split dosetreatment of MOVIPREP.

FIG. 2 is a graph showing the mean concentration of ascorbic acid(μg/ml) in plasma over time in subjects receiving the single dosetreatment of MOVIPREP.

EXPERIMENTAL

Pharmacokinetic Evaluation and Mass Balance Study

An investigation into the pharmacokinetics and mass balance of asolution in water of MOVIPREP powder for oral solution was carried outfollowing oral administration using single dose or split dose intake inhealthy male subjects.

Subjects:

The subjects were healthy male volunteers aged 18 to 45 years. Thesubjects' written informed consent was obtained. The subjects werewilling, able and competent to complete the procedure and to comply withthe study instructions. The subjects had to not meet any of theexclusion criteria. 24 subjects were randomly allocated into two groups:12 into the single-dose group and 12 into the split-dose group.

Study Medication:

The study medication administered was a solution in water of MOVIPREPpowder for oral solution. The total dose was 2 litres of the solutionfor each subject. The solution contains, per litre:

PEG3350: 100 g

Sodium Sulphate: 7.500 g

Ascorbic Acid: 4.700 g

Sodium Ascorbate: 5.900 g

Sodium chloride: 2.691 g

Potassium chloride: 1.015 g

Lemon-flavour and Sweetener

The 4.700 g ascorbic acid and 5.900 g sodium ascorbate together providethe equivalent of 9.944 g ascorbic acid. A 2 litre dose thus providesthe equivalent of 19.89 g of ascorbic acid.

Treatment Regimens:

The single dose group took the solution as follows:

2 L of solution were consumed between 17:00 and 20:00 on Day −1. Thefirst litre was consumed within the first hour, with at least 500 ml ofadditional clear fluid. The second litre was consumed within two hours,with at least 500 ml of additional clear fluid.

The split dose group took the solution as follows:

1 L of solution was consumed between 18:00 and 19:30 on Day −1. Thelitre was consumed within the 90 minutes, with at least 500 ml ofadditional clear fluid. The second litre was consumed between 07:00 and08:30 on Day 0 (the day on which a colonoscopy procedure would becarried out in a clinical situation). The litre was consumed within the90 minutes, with at least 500 ml of additional clear fluid.

Sample collection for monitoring of PK parameters in blood and recoveryof components in faeces and urine:

Urine and faeces were collected throughout the procedure. Cumulativecontent amounts of components under investigation in the urine wereobtained from measured concentrations of the components and measuredactual volume of urine. Similarly, the cumulative content amounts ofcomponents under investigation in the faeces were obtained from measuredconcentrations of the components and measured actual mass of faeces. Thedefined time points for analysis of urine and faeces were at Ohr, 2 hr,4 hr, 8 hr, 12 hr, 12.97 hr, 18 hr, 24 hr, 25.93 hr, 36 hr, 48 hr, 60hr, 72 hr and 120 hr after the start of intake of the first litre ofstudy medication. Blood samples were collected from the subjects atparticular time points through the procedure.

Sample Evaluation:

The cumulative amounts of ascorbic acid, PEG3350, chloride, sulphate,sodium and potassium in plasma, faeces and urine were evaluated. The PKprofiles of ascorbic acid, PEG3350, chloride, sulphate, sodium andpotassium in the plasma were evaluated. Plasma renin and aldosteronewere checked at all PK time points.

For higher accuracy, the analysis of the recovery of ascorbic acid wasextended to include also its metabolites dehydro-ascorbic acid andoxalic acid in urine and faeces.

Completion of Study:

Of the 12 subjects in the single-dose group, 4 had to be excluded fromthe analysis due to protocol violations, so 8 subjects were evaluated,

Of the 12 subjects in the split-dose group, 1 had to be excluded fromthe analysis due to protocol violations, so 11 subjects were evaluated.

Results:

General:

The mean cumulative recovery of ascorbic acid (including metabolitesdehydroascorbic acid and oxalic acid) and PEG3350 in faeces and urinewas comparable for the subjects in both treatment groups. The datacollected on the cumulative amount of chloride, sulphate, sodium andpotassium were comparable between the subjects in both treatment groupsinsofar as there was a continuous elimination in urine plus faeces (i.e.no plateau was reached). Furthermore, the PK parameters (AUC_(0-∞),AUC_(last), C_(max), K_(et), V_(d) and t_(1/2)) determined for ascorbicacid, sulphate, chloride, sulphate, sodium and potassium were comparablefor the subjects in the single dose and the split dose group; especiallythe values for AUC_(last) (i.e. exposure) were nearly identical for bothgroups.

Recovery and Mass Balance of Ascorbic Acid:

The ascorbic acid was to a significant extent excreted in faeces. Thecumulative recovery of ascorbic acid and its metabolites from 0 to 120hours after the start of intake of the first litre of study medicationis shown in Table 1 for the single-does group and in Table 2 for thesplit-dose group. In the final column of Tables 1 and 2, there is giventhe plasma concentration of ascorbate (not including its metabolites) atthe stated time points. That information in Tables 1 and 2 is taken fromthe graphs shown in FIGS. 1 and 2 respectively.

TABLE 1 Single Dose Group Time/hr Urine/g Faeces/g Total/g Plasma μg/ml0 0.000 ± 0.000  0.000 ± 0.000  0.00 ± 0.000 11.5 2 0.125 ± 0.0964 4.718 ± 3.5639  4.84 ± 3.643 43.0 4 0.456 ± 0.1193 11.961 ± 1.429112.42 ± 1.418 52.5 8 1.278 ± 0.2492 13.577 ± 1.2776 14.86 ± 1.243 38.012 1.472 ± 0.3116 13.587 ± 1.2882 15.06 ± 1.248 23.0 12.97 1.472 ±0.3116 13.587 ± 1.2882 15.06 ± 1.248 20.0 18 2.202 ± 0.4252 13.909 ±1.2864 16.11 ± 1.253 17.2 24 2.740 ± 0.5025 13.947 ± 1.2870 16.69 ±1.210 13.2 25.93 2.814 ± 0.5112 13.952 ± 1.2859 16.77 ± 1.218 13.2 363.162 ± 0.6042 13.952 ± 1.2860 17.11 ± 1.209 12.8 48 3.977 ± 0.719213.972 ± 1.2901 17.95 ± 1.369 12.3 60 4.605 ± 0.9177 13.982 ± 1.296418.59 ± 1.733 12.0 72 5.104 ± 1.1514 14.018 ± 1.3020 19.12 ± 1.920 12.3120 6.501 ± 1.9053 14.041 ± 1.3203 20.54 ± 2.723 Not measured From 12.97to 1.342 ± 0.4857  0.365 ± 0.4459 1.707 ± 0.780 N/A 25.93

TABLE 2 Split Dose Group Time/hr Urine/g Faeces/g Total/g Blood μg/ml 00.000 ± 0.000  0.000 ± 0.000  0.00 ± 0.000 10.5 2 0.248 ± 0.3552  2.356± 2.0088  2.60 ± 2.213 36.5 4 0.586 ± 0.3951  3.810 ± 2.4661  4.40 ±2.592 34.3 8 0.860 ± 0.5437  4.836 ± 2.4106  5.70 ± 2.607 25.0 12 0.860± 0.5437  4.836 ± 2.4106  5.70 ± 2.607 16.2 12.97 1.180 ± 0.6712  5.022± 2.4831  6.20 ± 2.772 15.0 18 2.220 ± 0.7555 10.239 ± 4.6259 12.46 ±4.885 25.5 24 3.323 ± 1.3183  1.010 ± 4.5147 14.33 ± 4.993 16.0 25.933.482 ± 1.3946 11.047 ± 4.5342 14.53 ± 5.123 15.8 36 4.351 ± 2.302311.062 ± 4.5147 15.41 ± 5.556 13.0 48 5.432 ± 3.3304 11.104 ± 4.549716.54 ± 6.200 11.6 60 6.228 ± 3.9837 11.109 ± 4.5519 17.34 ± 6.685 11.472 7.069 ± 4.5654 11.141 ± 4.5649 18.21 ± 7.104 11.4 120 9.123 ± 5.460511.195 ± 4.6225 20.32 ± 7.930 Not measured From 12.97 to 2.302 ± 1.2932 6.025 ± 2.4704 8.327 ± 3.113 N/A 25.93

Discussion

Of the 19.89 g ingested ascorbic acid equivalents contained in 2 litresof MOVIPREP solution 103.35% were found to be recovered in urine andfaeces of the single-dose group subjects after 120 hours, and 103.05%were found to be recovered in urine and faeces of the subjects in thesplit-dose group after 120 hours. There was no statistically significantdifference between the total recovered amount of ascorbic acid betweenthe two groups.

There was, however, a difference between the timing of the recovery andbetween the distribution of the ascorbic acid between urine and faeces.It is seen in Tables 1 and 2 that in the split dose group, thedistribution of the total recovered 20.32 g ascorbic acid between urineand faeces is in the ratio 9.123 g:11.1.95 g, ie 44.9%:55.1% (or 1:1.23)whilst, in the single dose group, the distribution of the totalrecovered 20.54 g ascorbic acid between urine and faeces is in the ratio6.501 g:14.041 g, ie 31.6% 68.4% (or 1:2.16).

The final column of each of Tables 1 and 2 shows the plasma level ofascorbate/ascorbic acid at the stated time points. The measurement doesnot include metabolites of ascorbic acid, and it does not take accountof ascorbate in other compartments in the body. Nevertheless, increasesin plasma ascorbate are clearly seen in the hours followingadministration of the solution.

In order to compare the recovery of ascorbic acid during the differentphases of the protocol, two time intervals were defined: the first timeinterval was between time zero, ie. the start of the intake of the firstlitre of study medication and time “x”, where “x” represents the minimalstarting time point of the intake of the second litre of studymedication for split dose group (from time 0 to 12.97 hrs). The secondtime interval was from time “x” to time 2x (from 12.97 to 25.93 hrs).

It is seen that, during the second time interval, 6.025 g of ascorbicacid are recovered from faeces of the split-dose group, compared with5.022 g during the first time interval. The 6.025 g in the second timeinterval is closer to being half of the 13,587 g seen over the firsttime interval in the single-dose group. That is to say that the seconddose of the split-dose treatment follows a similar time course to the(only) dose in the single-dose treatment.

The differences in the recovered amounts of components between the firstand the second time intervals are statistically significant for ascorbicacid (incl metabolites) in faeces (p=0.0078) and urine plus faeces(p=0.0078) for the single dose group subjects, and in urine (p=0.0020)and urine plus faeces (p=0.0322) of the split dose group subjects.

EXAMPLES

1. Bowel Cleansing Solutions

Example 1a—Contents of Solutions

The following bowel cleansing solutions of the invention were prepared.For solution A1, the components shown in Table 3 were combined in drypowder form and sealed in a sachet. The solution was then prepared bydissolving the contents in water to the volume stated in the penultimatecolumn. Solutions A2 and A3 were prepared in an analogous manner.

TABLE 3 Water Na₂SO₄ to Sol'n PEG3350/g (anhyd)/g NaCl/g KCl/g Vol/mlV(350)/ml A1 100 3 1.4 0.3 750 725 A2 100 6 1.6 0.7 750 915 A3 100 9 2.01.0 750 1080

For solution B1, the components shown in Table 4 were combined in drypowder form and sealed in respective sachets A and B as indicated in thetable. The solution was then prepared by mixing the contents of the twosachets together and then dissolving them in water to the volume statedin the penultimate column. Solutions B2 to B5 were prepared in ananalogous manner.

TABLE 4 Sachet A Sachet B Na₂SO₄ Sodium Ascorbic Magnesium Water toSol'n PEG3350/g (anhyd)/g NaCl/g KCl/g Ascorbate/g Acid/g Ascorbate/gVol/ml V(350)/ml B1 40 — 3.5 2.2 56.6 — — 500 2000 B2 20 — 2.7 1.3 33.920.1 — 500 1570 B3 40 — 2.8 1.3 33.9 20.1 — 500 1600 B4 40 6 2.8 2.033.9 — — 500 1700 B5 40 — 3.1 1.3 33.9 — 21.4 500 1700

The solutions additionally contained sweetener and flavouring sufficientto improve their palatability.

In the case of the solutions in Table 4, those components were in sachetA. The solutions were not optimised for palatability.

Example 1b—V(350) Osmolality Measurements

In order to assess the osmotic strength of the solutions, it wasdetermined how much water was required to provide a solution withmeasured osmolality of 350 mOsmol/kg from the amounts of the componentsin Tables 3 and 4.

To each solution prepared by dissolving the components in Tables 3 and 4above in 500 ml of deionised was added further deionised water until itreached an osmolality of 350 mOsmol/kg. After a volume was found in afirst experiment, a second experiment was carried out in which thevolume of water found in the first experiment was added to the contentsof a new sachet in one aliquot. It was then checked that the resultingsolution had an osmolality of 350+/−7 mOsmol/kg. In every case, it did.The volumes are recorded in Tables 3 and 4 in the final columns.Osmolalities were measured using an Advanced Instruments, Inc Model 3250osmometer. The osmometer was operated following standard instructions:after the device passes a calibration check, the “Low Range” osmolalityrange (0 to 2000 mOsmol/kg) is selected, and a sample tube containing250 μl of sample solution is placed in the freezing chamber. The “start”button is then pressed. When the measurement is completed, the devicedisplays the measurement result and that is recorded.

Example 2: Bowel Cleansing of Subjects

An open, randomised, single centre phase I study to investigate thepharmacodynamic effects (stool weight) of the various modified gutcleansing solutions. The study had two sequential parts (Part 1 and Part2). In both parts investigational medicinal product (IMP) wasadministered in the evening of Day 1 and the morning of Day 2. In Part 1of the study, three different solutions A given in the evening werecombined in turn with a fixed solution B given in the morning. Inaddition, one group of subjects received MOVIPREP®, as referenceproduct.

In Part 2 of the study, the selected solution A from Part 1 was given asthe evening dose in combination with four different solutions B as themorning dose. Stool output was assessed.

Number of Patients (Planned and Analysed):

Planned: at least 160 evaluable cases in the entire study (20 evaluablesubjects per treatment group)

Analysed: 161 evaluable cases (part A: 81 subjects; part B: 80subjects), Patients were subjected to inclusion and exclusion criteria.

Dosage Regimen:

Each subject received his/her solution regimen in the split dose intake:

-   -   Evening dose: Day 1; start intake between 17:00 and 18:00 pm for        an intake period of up to 2 hours after fasting from 14:00 pm.    -   Morning dose: Day 2; start intake between 7:00 and 8:00 am for        an intake period of up to 2 hours. 4 hours after complete intake        of the morning dose, the first meal was provided, but not before        completion of the planned safety laboratory blood drawing.

After the end of the intake of each dose of the investigationalsolution, the subjects were instructed to take further clear liquid(water).

Screened healthy subjects provided one stool collection after a completebowel motion in the 7 days before the planned admission to the unit forbaseline evaluation. After admission to the unit, all defecated faeceswere collected after each bowel movement. Stool appearance and weightwas determined for each collected stool fraction. Faecal samples weretaken until at least 15:00 pm on Day 4 and an attempt was made tocollect a final faecal sample prior to discharge from the phase 1 unit.

Solutions: Part 1:

TABLE 5a Na₂SO₄ Ascorbic Sodium Water to Sol'n PEG3350/g (anhyd)/gNaCl/g KCl/g acid ascorbate Vol/ml A2 100 6 1.6 0.7 — — 750 A3 100 9 2.01.0 — — 750 A4 75 5.6 2.0 0.8 — — 750 A-Mov 100 7.5 2.691 1.015 4.7 5.91000

TABLE 5b Sachet A Sachet B Na₂SO₄ Sodium Ascorbic Magnesium Water toSol'n PEG3350/g (anhyd)/g NaCl/g KCl/g Ascorbate/g Acid/g Ascorbate/gVol/ml B3 40 — 2.8 1.3 33.9 20.1 — 500 B-Mov 100 7.5 2.691 1.015 5.9 4.71000

The subjects were randomised into four groups (1:1:1:1), and given oneof the three solutions A2, A3 and A4 in Table 5a as the evening dose,followed by solution B3 as the morning dose, or (for the fourth group)given MOVIPREP solution for both doses (ie A-Mov followed by B-Mov).Solutions A2 and A3 are solutions of the invention. Solution A4 is areference solution. Solutions A-Mov and B-Mov are the commerciallyavailable MOVIPREP solution. Each of solutions A2 to A4 was taken in adose of 750 ml; the MOVIPREP solution was taken in a dose of 1000 ml asindicated in the product instructions.

In addition to the investigation formulations intake, the subjects wereinstructed to take further clear liquid (water). In the case ofsolutions A2 to A4, they were instructed to take 1750 mL of furtherclear liquid (875 ml, after the evening dose, and 875 mL after themorning dose). In the case of A-Mov, MOVIPREP®, they were instructed totake 1000 mL of further clear liquid (500 mL after the evening dose, and500 mL after the morning dose).

Solutions: Part 2:

TABLE 6a Na₂SO₄ Ascorbic Sodium Water to Sol'n PEG3350/g (anhyd)/gNaCl/g KCl/g acid ascorbate Vol/ml A3 100 9 2.0 1.0 — — 750

TABLE 6b Sachet A Sachet B Na₂SO₄ Sodium Ascorbic Magnesium Water toSol'n PEG3350/g (anhyd)/g NaCl/g KCl/g NaHCO₃/g Ascorbate/g Acid/gAscorbate/g Vol/ml B1 40 — 3.5 2.2 56.6 — — 500 B4 40 6   2.8 2.0 33.9 —— 500 B5 40 — 3.1 1.3 33.9 — 21.4 500 B6 29 4.8 1.4 0.9 2.2 — 23.3 — 500

The subjects were randomised into four groups (1:1:1:1), and givensolution A3 in Table 6a as the evening dose, followed by one of:solutions B1, B4, B5 and B6 as the morning dose. Solutions B1, B4 and B5are solutions of the invention. Solution B6 is a reference solution.

In addition to the investigation formulations intake, the subjects wereinstructed to take further clear liquid (water). In each case, they wereinstructed to take 1750 mL of further clear liquid (875 mL after theevening dose, and 875 mL after the morning dose).

Efficacy:

The primary variable in the clinical study was the stool weight outputgenerated by the investigational solutions (combined evening and morningdosing on Day 1 and Day 2) over 24 hours from the start of the intake ofthe evening solution. The reference value of the study was set to astool weight of approximately 2500 g or greater; which it is desired tobe reached in order to demonstrate positive pharmacodynamic effectsindicating a potential as a colon cleansing agent.

In addition to the primary trial variable mentioned above, stool outputwas separately measured and recorded for a) the time between when thesubject starts to take the evening dose (17:00 to 18:00 on Day 1) andthe time the subject starts to take the morning dose (7 am to Sam on Day2); and b) the time the subject starts to take the morning dose (7 am toSam on Day 2) and midnight on Day 2.

Results:

TABLE 7a Study Part 1: Stool Weight (g); full analysis set (FAS, N = 81)Treatment N 24 hr Median/g 24 hr Mean/g 24 hr STD/g A2 + B3 20 2981.33021.2 599.5 A3 + B3 21 3493.2 3386.1 602.74 A4 + B3 20 2796.80 2794688.27 A-Mov + B-Mov 20 3145.95 2973.7 479.41

In the table, the “24 hr Median” is the median stool output in the 24hours from the time the subject starts to take the evening dose (ie17:00 to 18:00 on Day 1 to the same time on Day 2); the “24 hr Mean” isthe mean of the 24 hour data, and the STD is the standard deviation.

TABLE 7b Study Part 1: Stool Weight (g); full analysis set (FAS, N = 81)pm stool am stool pm stool am stool Treatment N median/g median/g mean/gmean/g A2 + B3 20 925.8 2380.0 867.07 2196.9 A3 + B3 21 1178.5 2405.71184.34 2262.39 A4 + B3 20 826.7 2244.8 832.33 2005.25 A-Mov + B-Mov 201629.2 1536.4 1567.26 1453.83

The “pm stool median” is the median stool output between the time thesubject starts to take the evening dose (17:00 to 18:00 on Day 1) andthe time the subject starts to take the morning dose (7 am to 8 am onDay 2). The “am stool median” is the median stool output between thetime the subject starts to take the morning dose (7 am to 8 am on Day 2)and midnight on Day 2. The “pm stool mean” and “am stool mean” entriesare the corresponding mean values.

It is generally considered that a total stool output of approximately2500 g is required in order to achieve acceptable bowel cleansing. Astool output of approximately 2500 g or greater than that is thusindicative that a solution has good potential for use as a bowelcleansing solution. Both A2+B3 and A3+B3 resulted in a median stoolweight of significantly greater than 2500 g. The commercial MOVIPREP®solution also achieved a median stool output of in excess of 2500 g, aswas to be expected. The stool output was highest for A3+B3. Solution B3was therefore selected to be the morning solution for Part 2 of thestudy. The observed stool output was achieved for MOVIPREP with theingestion of 2 litres of investigational solution. For the A2+B3 andA3+B3 solutions, the mean stool weights were achieved using a totalinvestigational solution volume of 1250 ml.

Solutions A2 and A3 were effective in contributing to an effectivecleansing with any of the solutions with which they were used. It isseen from the “am stool median” and “pm stool median” figures that thestool output immediately after the ingestion of the A2 and A3 solutionswas less copious than after the B solutions. The A2 and A3 solutionscontributed to the effective bowel cleansing. Given that the subjectwill often wish to sleep between taking the first bowel cleansingsolution and the second solution, it may be advantageous for the firstcleansing solution to result in a slightly lower stool output than thesecond cleansing solution.

TABLE 8a Study Part 2: Stool Weight (g); full analysis set (FAS, N = 80)Treatment N 24 hr Median/g 24 hr Mean/g 24 hr STD/g A3 + B1 20 3128.92898.2 856.6 A3 + B4 20 2546 2453.3 775.1 A3 + B5 20 2440.1 2501.21000.3 A3 + B6 20 2466.8 2485.6 496.1

TABLE 8b Study Part 2: Stool Weight (g); full analysis set (FAS, N = 80)pm stool am stool pm stool am stool Treatment N median/g median/g mean/gmean/g A3 + B1 20 1170.0 2146.4 1087.59 1846.41 A3 + B4 20 1156.5 1467.21114.64 1370.69 A3 + B5 20 1091.1 1448.6 1039.42 1574.65 A3 + B6 201210.7 1436.2 1163.93 1402.64

A3+B1 and A3+B4 resulted in a 24 hour median stool output weight ofgreater than 2500 g. For the combination A3+B5, the median stool outputwas just under 2500 g, but the mean stool output was over 2500 g. Thus,all of the solution combinations of the invention (A3+B1, A3+B4 andA3+B5) resulted in a 24 hour mean or median stool output weight ofgreater than 2500 g.

Considering the data from tables 7a, 7b, 8a and 8b together, B1, B3, B4and B5 solutions have been shown to be effective bowel cleansingsolutions when used in combination with any other solution with whichthey were used. The particularly copious stool output seen in the “amstool mean” figures shows that the solutions are especially effective.

In the case of A3+B1, the median stool weight was significantly greaterthan 2500 g. It is again noteworthy that the mean stool weights wereachieved using a total investigational solution volume of only 1250 ml.

Solution A3 in combination with reference solution B6 resulted in stooloutput that was not statistically significantly different from 2500 g.

We claim:
 1. A colon cleansing composition, comprising: 52.5 to 187.5 gPEG having an average molecular weight of 2500 to 4500 Da; and 3.75 to15 g of one or more alkali metal sulphates, alkaline earth metalsulphates or a mixture thereof; wherein the composition is configuredfor colon cleansing in an ingestion volume of 400 to 600 ml of water;and wherein the composition is free from ascorbate components.
 2. Thecomposition of claim 1, wherein the ingestion volume is about 500 ml ofwater.
 3. The composition of claim 1, wherein the PEG is in the range of75 to 150 g.
 4. The composition of claim 1, wherein the PEG is in therange of 90 to 112.5 g.
 5. The composition of claim 1, wherein the PEGis in the amount of 100 g.
 6. The composition of claim 1, wherein theone or more alkali metal sulphates, alkaline earth metal sulphates orthe mixture thereof is in the range of 6 to 15 g.
 7. The composition ofclaim 1, wherein the one or more alkali metal sulphates, alkaline earthmetal sulphates or the mixture thereof is in the amount of 9 g.
 8. Thecomposition of claim 1, further comprising: 0.75 to 2.25 g sodiumchloride; and 0.075 to 2.25 g potassium chloride.
 9. The composition ofclaim 1, further comprising a sweetener wherein the sweetener issucralose.
 10. The composition of claim 1, further comprising citricacid.
 11. The composition of claim 1, further comprising: 1.5 to 2.25 gsodium chloride, 0.15 to 1.5 g potassium chloride, sucralose, and citricacid; wherein: the PEG is in the amount of 100 g and the averagemolecular weight is 3000 to 4000 Da; and the one or more alkali metalsulphates, alkaline earth metal sulphates or the mixture thereof is inthe amount of 9 g sodium sulphate.
 12. The composition of claim 1,wherein the polyethylene glycol is present at a level between 77.8% and98.0% w/w; and the sulphate component is present at a level between 2.0%and 22.2% w/w.
 13. A colon cleansing solution, comprising: 130 to 250 gper liter PEG having an average molecular weight of 2500 to 4500 Da; and15 to 20 g per liter of one or more alkali metal sulphates, alkalineearth metal sulphates or a mixture thereof; and 400 to 600 ml water;wherein the solution is free from ascorbate components.
 14. The solutionof claim 13, further comprising: 1.0 to 4.0 g per liter sodium chloride;and 0.1 to 3.0 g per liter potassium chloride.
 15. The solution of claim13, further comprising a sweetener wherein the sweetener is sucralose.16. The solution of claim 13, further comprising citric acid.
 17. Amethod of cleansing a colon of a subject comprising administering thesolution of claim
 13. 18. A method of cleansing a colon of a subjectcomprising administering the solution of claim 13 in combination with adifferent colon cleansing solution.
 19. A colon cleansing solution,consisting essentially of: 130 to 250 g per liter PEG having an averagemolecular weight of 2500 to 4500 Da; 15 to 20 g per liter of one or morealkali metal sulphates, alkaline earth metal sulphates or a mixturethereof; 400-600 ml water; optionally 0.5 to 5.0 g per liter sodiumchloride; optionally 0.1 to 3.0 g per liter potassium chloride;optionally one or more flavoring agents; and optionally one or moresweeteners; wherein the solution is free from ascorbate components.